9-[(substituted glycyl)amido)]-6-demethyl-6-deoxytetracyclines

ABSTRACT

The invention provides compounds of the formula:  &lt;IMAGE&gt;  wherein R, R1 and Y are defined in the specification. The compounds are useful for the production of 6-demethyl-6-deoxytracycline derivatives.

This is a divisional of application Ser. No. 07/928,590 filed on Aug.13, 1992 now U.S. Pat. No. 5,442,059.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to novel [4S-(4alpha,12aalpha)]-4-(dimethylamino)-9-[[(substitutedamino)substituted]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidesherein after called 9-[(substitutedglycyl)amido]-6-demethyl-6-deoxytetracyclines, which exhibit antibioticactivity against a wide spectrum of organisms including organisms whichare resistant to tetracyclines and are useful as antibiotic agents.

The invention also relates to novel9-[(haloacyl)amido]-6-demethyl-6-deoxytetracycline intermediates usefulfor making the novel compounds of the present invention and to novelmethods for producing the novel compounds and intermediate compounds.

SUMMARY OF THE INVENTION

This invention is concerned with novel 9-[(substitutedglycyl)amido]-6-demethyl-6-deoxytetracyclines represented by formula Iand II, which have antibacterial activity; with methods of treatinginfectious diseases in warm blooded animals employing these newcompounds; with pharmaceutical preparations containing these compounds;with novel intermediate compounds and processes for the production ofthese compounds. More particularly, this invention is concerned withcompounds of formula I and II which have enhanced in vitro and in vivoantibacterial activity against tetracycline resistant strains as well asa high level of activity against strains which are normally susceptibleto tetracyclines. ##STR2##

In formula I and II, R is selected from hydrogen; straight or branched(C₁ -C₈)alkyl group selected from methyl, ethyl, propyl, isopropyl,butyl, isobutyl, pentyl, hexyl, heptyl and octyl; α-mercapto(C₁-C₄)alkyl group selected from mercaptomethyl, α-mercaptoethyl,α-mercapto-1-methylethyl, α-mercaptopropyl and α-mercaptobutyl;α-hydroxy(C₁ -C₄)alkyl group selected from hydroxymethyl,α-hydroxyethyl, α-hydroxy-1-methylethyl, α-hydroxypropyl andα-hydroxybutyl; carboxyl(C₁ -C₈)alkyl group; (C₆ -C₁₀)aryl groupselected from phenyl, α-naphthyl and β-naphthyl; substituted(C₆-C₁₀)aryl group (substitution selected from hydroxy, halogen, (C₁-C₄)alkoxy, trihalo(C₁ -C₃) alkyl, nitro, amino, cyano, (C₁-C₄)alkoxycarbonyl, (C₁ -C₃)alkylamino and carboxy); (C₇ -C₉)aralkylgroup selected from benzyl, 1-phenylethyl, 2-phenylethyl andphenylpropyl; substituted(C₇ -C₉)aralkyl group [substitution selectedfrom halo, (C₁ -C₄)alkyl, nitro, hydroxy, amino, mono- or di-substituted(C₁ -C₄)alkylamino, (C₁ -C₄)alkoxy, (C₁ -C₄)alkylsulfonyl, cyano andcarboxy];

R¹ is selected from hydrogen and (C₁ -C₆)alkyl selected from methyl,ethyl propyl, isopropyl, butyl, isobutyl, pentyl and hexyl;

when R does not equal R¹ the stereochemistry of the asymmetric carbon(i.e. the carbon bearing the W substituent) maybe be either the racemate(DL) or the individual enantiomers (L or D);

W is selected from amino; hydroxylamino; (C₁ -C₁₂) straight or branchedalkyl monosubstituted amino group substitution selected from methyl,ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl,1,1-dimethylethyl, n-pentyl, 2-methylbutyl, 1,1-dimethylpropyl,2,2-dimethylpropyl, 3-methylbutyl, n-hexyl, 1-methylpentyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3-methylpentyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 1-methyl-1-ethylpropyl, heptyl, octyl, nonyl, decyl,undecyl and dodecyl and the diastereomers and enantiomers of saidbranched alkyl monosubstituted amino group; (C₃ -C₈)cycloalkylmonosubstituted amino group substitution selected from cyclopropyl,trans-1,2-dimethylcyclopropyl, cis-1,2-dimethylcyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,bicyclo[2.2.1]hept-2-yl, and bicyclo[2.2.2]oct-2-yl and thediastereomers and enantiomers of said (C₃ -C₈)cycloalkyl monosubstitutedamino group; [(C₄ -C₁₀)cycloalkyl]alkyl monosubstituted amino groupsubstitution selected from (cyclopropyl)methyl, (cyclopropyl)ethyl,(cyclobutyl)methyl, (trans-2-methylcyclopropyl)methyl, and(cis-2-methylcyclobutyl)methyl; (C₃ -C₁₀)alkenyl monosubstituted aminogroup substitution selected from allyl, 3-butenyl, 2-butenyl (cis ortrans), 2-pentenyl, 4-octenyl, 2,3-dimethyl-2-butenyl,3-methyl-2-butenyl 2-cyclopentenyl and 2-cyclohexenyl; (C₆ -C₁₀)arylmonosubstituted amino group substitution selected from phenyl andnaphthyl; (C₇ -C₁₀)aralkylamino group substitution selected from benzyl,2-phenylethyl, 1-phenylethyl, 2-(naphthyl)methyl, 1-(naphthyl)methyl andphenylpropyl; substituted (C₆ -C₁₀)aryl monosubstituted amino group[substitution selected from (C₁ -C₅)acyl, (C₁ -C₅)acylamino, (C₁-C₄)alkyl, mono or disubstituted (C₁ -C₈)alkylamino, (C₁ -C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁ -C₄)alkylsulfonyl, amino, carboxy, cyano,halogen, hydroxy, nitro and trihalo(C₁ -C₃)alkyl]; straight or branchedsymmetrical disubstituted (C₂ -C₁₄)alkylamino group substitutionselected from dimethyl, diethyl, diisopropyl, di-n-propyl, di-n-butyland diisobutyl; symmetrical disubstituted (C₃ -C₁₄)cycloalkylamino groupsubstitution selected from dicyclopropyl, dicyclobutyl, dicyclopentyl,dicylohexyl and dicycloheptyl; straight or branched unsymmetricaldisubstituted (C₃ -C₁₄)alkylamino group wherein the total number ofcarbons in the substitution is not more than 14; unsymmetricaldisubstituted (C₄ -C₁₄)cycloalkylamino group wherein the total number ofcarbons in the substitution is not more than 14; (C₂ -C₈)azacycloalkyland substituted (C₂ -C₈)azacycloalkyl group substitution selected fromaziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, 4-methylpiperidinyl,2-methylpyrrolidinyl, cis-3,4-dimethylpyrrolidinyl,trans-3,4-dimethylpyrrolidinyl, 2-azabicyclo[2.1.1]hex-2-yl,5-azabicyclo[2.1.1]hex-5-yl, 2-azabicyclo[2.2.1]hept-2-yl,7-azabicyclo[2.2.1]hept-7-yl, and 2-azabicyclo[2.2.2]oct-2-yl and thediastereomers and enantiomers of said (C₂ -C₈)azacycloalkyl andsubstituted (C₂ -C₈)azacycloalkyl group; 1-azaoxacycloalkyl groupselected from morpholinyl and 1-aza-5-oxocycloheptane; substituted1-azaoxacycloalkyl group substitution selected from 2-(C₁-C₃)alkylmorpholinyl, 3-(C₁ -C₃)alkylisooxazolidinyl, tetrahydrooxazinyland 3,4-dihydrooxazinyl; [1,n]-diazacycloalkyl and substituted[1,n]-diazacycloalkyl group selected from piperazinyl, 2-(C₁-C₃)alkylpiperazinyl, 4-(C₁ -C₃)alkylpiperazinyl,2,4-dimethylpiperazinyl, 4-(C₁ -C₄)alkoxypiperazinyl, 4-(C₆-C₁₀)aryloxypiperazinyl, 4-hydroxypiperazinyl,2,5-diazabicyclo[2.2.1]hept-2-yl,2,5-diaza-5-methylbicyclo[2.2.1]hept-2-yl,2,3-diaza-3-methylbicyclo[2.2.2]oct-2-yl, and2,5-diaza-5,7-dimethylbicyclo[2.2.2]oct-2-yl and the diastereomers orenantiomers of said 1,n]-diazacycloalkyl and substituted1,n]-diazacycloalkyl group; 1-azathiacycloalkyl and substituted1-azathiacycloalkyl group selected from thiomorpholinyl, 2-(C₁-C₃)alkylthiomorpholinyl and 3-(C₃ -C₆)cycloalkylthiomorpholinyl;N-azolyl and substituted N-azolyl group selected from 1-imidazolyl,2-(C₁ -C₃)alkyl-1-imidazolyl, 3-(C₁ -C₃)alkyl-1-imidazolyl, 1-pyrrolyl,2-(C₁ -C₃)alkyl-1-pyrrolyl, 3-(C₁ -C₃)alkyl-1-pyrrolyl, 1-pyrazolyl,3-(C₁ -C₃)alkyl-1-pyrazolyl, indolyl, 1-(1,2,3-triazolyl), 4-(C₁-C₃)alkyl-1-(1,2,3-triazolyl), 5-(C₁ -C₃)alkyl-1-(1,2,3-triazolyl),4-(1,2,4-triazolyl, 1-tetrazolyl, 2-tetrazolyl and benzimidazolyl;(heterocycle)amino group said heterocycle selected from 2- or 3-furanyl,2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 5-pyridazinyl, 2-pyrazinyl,2-(imidazolyl), (benzimidazolyl), and (benzothiazolyl) and substituted(heterocycle)amino group (substitution selected from straight orbranched (C₁ -C₆)alkyl); (heterocycle)methylamino group selected from 2-or 3-furylmethylamino, 2- or 3-thienylmethylamino, 2-, 3- or4-pyridylmethylamino, 2- or 5-pyridazinylmethylamino,2-pyrazinylmethylamino, 2-(imidazolyl)methylamino,(benzimidazolyl)methylamino, and (benzothiazolyl)methylamino andsubstituted (heterocycle)methylamino group (substitution selected fromstraight or branched (C₁ -C₆)alkyl); carboxy(C₂ -C₄)alkylamino groupselected from aminoacetic acid, α-aminopropionic acid, β-aminopropionicacid, α-butyric acid, and β-aminobutyric acid and the enantiomers ofsaid carboxy(C₂ -C₄)alkylamino group; (C₁ -C₄)alkoxycarbonylamino groupsubstitution selected from methoxycarbonyl, ethoxycarbonyl,allyloxycarbonyl, propoxycarbonyl, isoproproxycarbonyl,1,1-dimethylethoxycarbonyl, n-butoxycarbonyl, and2-methylpropoxycarbonyl; (C₁ -C₄)alkoxyamino group substitution selectedfrom methoxy, ethoxy,n-propoxy, 1-methylethoxy, n-butoxy,2-methylpropoxy, and 1,1-dimethylethoxy; (C₃ -C₈)cycloalkoxyamino groupselected from cyclopropoxy, trans-1,2-dimethylcyclopropoxy,cis-1,2-dimethylcyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy,cycloheptoxy, cyclooctoxy, bicyclo[2.2.1]hept-2-yloxy, andbicyclo[2.2.2]oct-2-yloxy and the diastereomers and enantiomers of said(C₃ -C₈)cycloalkoxyamino group; (C₆ -C₁₀)aryloxyamino group selectedfrom phenoxyamino, 1-naphthyloxyamino and 2-naphthyloxyamino; (C₇-C₁₁)arylalkoxyamino group substitution selected from benzyloxy,2-phenylethoxy, 1-phenylethoxy, 2-(naphthyl)methoxy, 1-(naphthyl)methoxyand phenylpropoxy;

R² is selected from hydrogen; straight or branched (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl; (C₆ -C₁₀)arylgroup selected from phenyl, α-naphthyl or β-naphthyl; (C₇ -C₉)aralkylgroup such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; aheterocycle group selected from a five membered aromatic or saturatedring with one N, O, S or Se heteroatom optionally having a benzo orpyrido ring fused thereto: ##STR3## such as pyrrolyl, N-methylindolyl,indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl, thienyl,benzothienyl or selenazolyl, or a five membered aromatic ring with twoN, O, S or Se heteroatoms optionally having a benzo or pyrido ring fusedthereto: ##STR4## such as imidazolyl, pyrazolyl, benzimidazolyl,oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl,3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl, or a fivemembered saturated ring with one or two N, O, S or Se heteroatoms and anadjacent appended heteroatom: ##STR5## (A is selected from hydrogen;straight or branched (C₁ -C₄)alkyl; C₆ -aryl; substituted C₆ -aryl(substitution selected from halo, (C₁ -C₄)alkoxy, trihalo(C₁ -C₃)alkyl,nitro, amino, cyano, (C₁ -C₄)alkoxycarbonyl, (C₁ -C₃)alkylamino orcarboxy); (C₇ -C₉)aralkyl group selected from benzyl, 1-phenylethyl,2-phenylethyl or phenylpropyl)

such as γ-butyrolactam, γ-butyrolactone, imidazolidinone orN-aminoimidazolidinone, or a six membered aromatic ring with one tothree N heteroatoms such as pyridyl, pyridazinyl, pyrazinyl,sym-triazinyl, unsym-triazinyl, pyrimidinyl or (C₁ -C₃)alkylthiopyridazinyl, or a six membered saturated ring with one or twoN, O, S or Se heteroatoms and an adjacent appended O heteroatom such as2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-2-dioxo-1-piperazinyl,2-dioxomorpholinyl, 2-dioxothiomorpholinyl; or --(CH₂)_(n) COOR⁴ wheren=0-4 and R⁴ is selected from hydrogen; straight or branched (C₁-C₃)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl;or (C₆ -C₁₀)aryl group selected from phenyl, α-naphthyl, or β-naphthyl;R³ is selected from hydrogen; straight or branched (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl; (C₆ -C₁₀)arylgroup selected from phenyl, α-naphthyl or β-naphthyl; (C₇ -C₉)aralkylgroup such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; aheterocycle group selected from a five membered aromatic or saturatedring with one N, O, S or Se heteroatom optionally having a benzo orpyrido ring fused thereto: ##STR6## such as pyrrolyl, N-methylindolyl,indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl, thienyl,benzothienyl or selenazolyl, or a five membered aromatic ring with twoN, O, S or Se heteroatoms optionally having a benzo or pyrido ring fusedthereto: ##STR7## such as imidazolyl, pyrazolyl, benzimidazolyl,oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl,3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl, or a fivemembered saturated ring with one or two N, O, S or Se heteroatoms and anadjacent appended O heteroatom: ##STR8## (A is selected from hydrogen;straight or branched (C₁ -C₄)alkyl; C₆ -aryl; substituted C₆ -aryl(substitution selected from halo, (C₁ -C₄)alkoxy, trihalo(C₁ -C₃)alkyl,nitro, amino, cyano, (C₁ -C₄)alkoxycarbonyl, (C₁ -C₃)alkylamino orcarboxy); (C₇ -C₉)aralkyl group selected from benzyl, 1-phenylethyl,2-phenylethyl or phenylpropyl)

such as γ-butyrolactam, γ-butyrolactone, imidazolidinone orN-aminoimidazolidinone, or a six membered aromatic ring with one tothree N heteroatoms such as pyridyl, pyridazinyl, pyrazinyl,sym-triazinyl, unsym-triazinyl, pyrimidinyl or (C₁-C₃)alkylthiopyridazinyl, or a six membered saturated ring with one ortwo N, O, S or Se heteroatoms and an adjacent appended O heteroatom suchas 2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-2-dioxo-1-piperazinyl,2-dioxomorpholinyl, 2-dioxothiomorpholinyl; or --(CH₂)_(n) COOR⁴ wheren=0-4 and R⁴ is selected from hydrogen; straight or branched (C₁-C₃)alkyl selected from methyl, ethyl, n-propyl or 1-methylethyl; or (C₆-C₁₀)aryl selected from phenyl, α-naphthyl or β-naphthyl; with theproviso that R² and R³ cannot both be hydrogen;

or R² and R³ taken together are --(CH₂)₂ B(CH₂)₂ --, wherein B isselected from (CH₂)_(n) and n=0-1, --NH, --N(C₁ -C₃)alkyl [straight orbranched], --N(C₁ -C₄)alkoxy, oxygen, sulfur or substituted congenersselected from (L or D)proline, ethyl(L or D)prolinate, morpholine,pyrrolidine or piperidine; and the pharmacologically acceptable organicand inorganic salts or metal complexes.

Preferred compounds are compounds according to the above formula I andII wherein: R is selected from hydrogen; straight or branched (C₁-C₈)alkyl group selected from methyl, ethyl, propyl, isopropyl, butyl,isobutyl, pentyl, hexyl, heptyl and octyl; α-mercapto(C₁ -C₄)alkyl groupselected from mercaptomethyl, α-mercaptoethyl, α-mercapto-1-methylethyl,α-mercaptopropyl and α-mercaptobutyl; α-hydroxy(C₁ -C₄)alkyl groupselected from hydroxymethyl, α-hydroxyethyl, α-hydroxy-1-methylethyl,α-hydroxypropyl and α-hydroxybutyl; carboxyl(C₁ -C₈)alkyl group; (C₆-C₁₀)aryl group selected from phenyl, α-naphthyl and β-naphthyl; (C₇-C₉)aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl andphenylpropyl; substituted(C₇ -C₉)aralkyl group [substitution selectedfrom halo, (C₁ -C₄)alkyl, nitro, hydroxy, amino, mono- or di-substituted(C₁ -C₄)alkylamino, (C₁ -C₄)alkoxy, (C₁ -C₄)alkylsulfonyl, cyano andcarboxy];

R¹ is selected from hydrogen and (C₁ -C₆)alkyl selected from methyl,ethyl propyl, isopropyl, butyl, isobutyl, pentyl and hexyl;

when R does not equal R¹ the stereochemistry of the asymmetric carbon(i.e. the carbon bearing the W substituent) maybe be either the racemate(DL) or the individual enantiomers (L or D);

W is selected from amino; hydroxylamino; (C₁ -C₁₂) straight or branchedalkyl monosubstituted amino group substitution selected from methyl,ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl,1,1-dimethylethyl, n-pentyl, 2-methylbutyl, 1,1-dimethylpropyl,2,2-dimethylpropyl, 3-methylbutyl, n-hexyl, 1-methylpentyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3-methylpentyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 1-methyl-1-ethylpropyl, heptyl, octyl, nonyl, decyl,undecyl and dodecyl and the diastereomers and enantiomers of saidbranched alkyl monosubstituted amino group; (C₃ -C₈)cycloalkylmonosubstituted amino group substitution selected from cyclopropyl,trans-1,2-dimethylcyclopropyl, cis-1,2-dimethylcyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,bicyclo[2.2.1]hept-2-yl, and bicyclo[2.2.2]oct-2-yl and thediastereomers and enantiomers of said (C₃ -C₈)cycloalkyl monosubstitutedamino group; [(C₄ -C₁₀)cycloalkyl]alkyl monosubstituted amino groupsubstitution selected from(cyclopropyl)methyl, (cyclopropyl)ethyl,(cyclobutyl)methyl, (trans-2-methylcyclopropyl)methyl, and(cis-2-methylcyclobutyl)methyl; (C₃ -C₁₀)alkenyl monosubstituted aminogroup substitution selected from allyl, 3-butenyl, 2-butenyl (cis ortrans), 2-pentenyl, 4-octenyl, 2,3-dimethyl-2-butenyl,3-methyl-2-butenyl 2-cyclopentenyl and 2-cyclohexenyl; (C₆ -C₁₀)arylmonosubstituted amino group substitution selected from phenyl andnaphthyl; (C₇ -C₁₁)aralkylamino group substitution selected from benzyl,2-phenylethyl, 1-phenylethyl, 2-(naphthyl)methyl, 1-(naphthyl)methyl andphenylpropyl; straight or branched symmetrical disubstituted (C₂-C₁₄)alkylamino group substitution selected from dimethyl, diethyl,diisopropyl and di-n-propyl; symmetrical disubstituted (C₃-C₁₄)cycloalkylamino group substitution selected from dicyclopropyl,dicyclobutyl, dicyclopentyl, dicylohexyl and dicycloheptyl; straight orbranched unsymmetrical disubstituted (C₃ -C₁₄)alkylamino group whereinthe total number of carbons in the substitution is not more than 14;unsymmetrical disubstituted (C₄ -C₁₄)cycloalkylamino group wherein thetotal number of carbons in the substitution is not more than 14; (C₂-C₈)azacycloalkyl and substituted (C₂ -C₈)azacycloalkyl group selectedfrom aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,4-methylpiperidinyl, 2-methylpyrrolidinyl, cis-3,4-dimethylpyrrolidinyl,trans-3,4-dimethylpyrrolidinyl, 2-azabicyclo[2.1.1]hex-2-yl,5-azabicyclo[2.1.1]hex-5-yl, 2-azabicyclo[2.2.1]hept-2-yl,7-azabicyclo[2.2.1]hept-7-yl, and 2-azabicyclo[2.2.2]oct-2-yl and thediastereomers and enantiomers of said (C₂ -C₈)azacycloalkyl andsubstituted (C₂ -C₈)azacycloalkyl group; 1-azaoxacycloalkyl groupselected from morpholinyl and 1-aza-5-oxacycloheptane; substituted1-azaoxacycloalkyl group selected from 2-(C₁ -C₃)alkylmorpholinyl, 3-(C₁-C₃)alkylisoxazolidinyl, tetrahydrooxazinyl and 3,4-dihydrooxazinyl;[1,n]-diazacycloalkyl and substituted [1,n]-diazacycloalkyl groupselected from piperazinyl, 2-(C₁ -C₄)alkylpiperazinyl, 4-(C₁-C₃)alkylpiperazinyl, 2,4-dimethylpiperazinyl, 4-(C₁-C₃)alkoxypiperazinyl, 4-(C₆ -C₁₀)aryloxypiperazinyl,4-hydroxypiperazinyl, 2,5-diazabicyclo-[2.2.1]hept-2-yl,2,5-diaza-5-methylbicyclo-[2.2.1]hept-2-yl,2,3-diaza-3-methylbicyclo[2.2.2]-oct-2-yl, and2,5-diaza-5,7-dimethylbicyclo[2.2.2]oct-2-yl and the diastereomers orenantiomers of said [1,n]-diazacycloalkyl and substituted[1,n]-diazacycloalkyl group; 1-azathiacycloalkyl and substituted1-azathiacycloalkyl group selected from thiomorpholinyl, 2-(C₁-C₃)alkylthiomorpholinyl and 3-(C₃ -C₆)cycloalkylthiomorpholinyl;N-azolyl and substituted N-azolyl group selected from 1-imidazolyl,2-(C₁ -C₃)alkyl-1-imidazolyl, 3-(C₁ -C₃)alkyl-1-imidazolyl, 1-pyrrolyl,2-(C₁ -C₃)alkyl-1-pyrrolyl, 3-(C₁ -C₃)alkyl-1-pyrrolyl, 1-pyrazolyl,3-(C₁ -C₃)alkyl-1-pyrazolyl, indolyl, 1-(1,2,3-triazo- lyl),4-alkyl-1-(1,2,3-triazolyl), 5-(C₁ -C₃)alkyl-1- (1,2,3-triazolyl),4-(1,2,4-triazolyl, 1-tetrazolyl, 2-tetrazolyl and benzimidazolyl;(heterocycle)amino group said heterocycle selected from 2- or 3-furanyl,2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 5-pyridazinyl, 2-pyrazinyl,2-(imidazolyl), (benzimidazolyl), and (benzothiazolyl) and substituted(heterocycle)amino group (substitution selected from straight orbranched (C₁ -C₆)alkyl); (heterocycle)methylamino group selected from 2-or 3-furylmethylamino, 2- or 3-thienylmethylamino, 2-, 3- or4-pyridylmethylamino, 2- or 5-pyridazinylmethylamino,2-pyrazinylmethylamino, 2-(imidazolyl)methylamino,(benzimidazolyl)methylamino, and (benzothiazolyl)methylamino andsubstituted (heterocycle)methylamino group (substitution selected fromstraight or branched (C₁ -C₆)alkyl); carboxy(C₂ -C₄)alkylamino groupselected from aminoacetic acid, α-aminopropionic acid, β-aminopropionicacid, α-butyric acid, and β-aminobutyric acid and the enantiomers ofsaid carboxy(C₂ -C₄)alkylamino group; (C₁ -C₄)alkoxycarbonylamino groupsubstitution selected from methoxycarbonyl, ethoxycarbonyl,allyloxycarbonyl, propoxycarbonyl, isoproproxycarbonyl,1,1-dimethylethoxycarbonyl, n-butoxycarbonyl, and2-methylpropoxycarbonyl; (C₁ -C₄)alkoxyamino group substitution selectedfrom methoxy, ethoxy,n-propoxy, 1-methylethoxy, n-butoxy,2-methylpropoxy, and 1,1-dimethylethoxy; (C₃ -C₈)cycloalkoxyamino groupsubstitution selected from cyclopropoxy, trans-1,2-dimethylcyclopropoxy,cis-1,2-dimethylcyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy,cycloheptoxy, cyclooctoxy, bicyclo[2.2.1]hept-2-yloxy, andbicyclo[2.2.2]oct-2-yloxy and the diastereomers and enantiomers of said(C₃ -C₈)cycloalkoxyamino group; (C₆ -C₁₀)aryloxyamino group selectedfrom phenoxyamino, 1-naphthyloxyamino and 2-naphthyloxyamino; (C₇-C₁₁)arylalkoxyamino group substitution selected from benzyloxy,2-phenylethoxy, 1-phenylethoxy, 2-(naphthyl)methoxy, 1-(naphthyl)methoxyand phenylpropoxy;

R² is selected from hydrogen; straight or branched (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl; (C₆ -C₁₀)arylgroup selected from phenyl, α-naphthyl or β-naphthyl; (C₇ -C₉)aralkylgroup selected from benzyl, 1-phenylethyl, 2-phenylethyl orphenylpropyl; a heterocycle group selected from a five membered aromaticor saturated ring with one N, O, S or Se heteroatom optionally having abenzo or pyrido ring fused thereto: ##STR9## such as pyrrolyl,N-methylindolyl, indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl, thienyl,benzothienyl or selenazolyl, or a five membered aromatic ring with twoN, O, S or Se heteroatoms optionally having a benzo or pyrido ring fusedthereto: ##STR10## such as imidazolyl, pyrazolyl, benzimidazolyl,oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl,3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl, or a fivemembered saturated ring with one or two N, O, S or Se heteroatoms and anadjacent appended heteroatom: ##STR11## (A is selected from hydrogen;straight or branched (C₁ -C₄)alkyl; C₆ -aryl; substituted C₆ -aryl(substitution selected from halo, (C₁ -C₄)alkoxy, trihalo(C₁ -C₃)alkyl,nitro, amino, cyano, (C₁ -C₄)alkoxycarbonyl, (C₁ -C₃)alkylamino orcarboxy); (C₇ -C₉)aralkyl group selected from benzyl, 1-phenylethyl,2-phenylethyl or phenylpropyl)

such as γ-butyrolactam, γ-butyrolactone, imidazolidinone orN-aminoimidazolidinone, or a six membered aromatic ring with one tothree N heteroatoms such as pyridyl, pyridazinyl, pyrazinyl,sym-triazinyl, unsym-triazinyl, pyrimidinyl or (C₁-C₃)alkylthiopyridazinyl, or a six membered saturated ring with one ortwo N, O, S or Se heteroatoms and an adjacent appended O heteroatom suchas 2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-2-dioxo-1-piperazinyl,2-dioxomorpholinyl, 2-dioxothiomorpholinyl; or --(CH₂)_(n) COOR⁴ wheren=0-4 and R⁴ is selected from hydrogen; straight or branched (C₁-C₃)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl;or (C₆ -C₁₀)aryl group selected from phenyl, α-naphthyl, β-naphthyl; R³is selected from hydrogen; straight or branched (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl; (C₆ -C₁₀)arylgroup selected from phenyl, α-naphthyl or β-naphthyl; (C₇ -C₉)aralkylgroup such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; aheterocycle group selected from a five membered aromatic or saturatedring with one N, O, S or Se heteroatom optionally having a benzo orpyrido ring fused thereto: ##STR12## such as pyrrolyl, N-methylindolyl,indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl, thienyl,benzothienyl or selenazolyl, or a five membered aromatic ring with twoN, O, S or Se heteroatoms optionally having a benzo or pyrido ring fusedthereto: ##STR13## such as imidazolyl, pyrazolyl, benzimidazolyl,oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl,3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl, or a fivemembered saturated ring with one or two N, O, S or Se heteroatoms and anadjacent appended O heteroatom: ##STR14## (A is selected from hydrogen;straight or branched (C₁ -C₄)alkyl; C₆ -aryl; substituted C₆ -aryl(substitution selected from halo, (C₁ -C₄)alkoxy, trihalo(C₁ -C₃ )alkyl,nitro, amino, cyano, (C₁ -C₄)alkoxycarbonyl, (C₁ -C₃)alkylamino orcarboxy); (C₇ -C₉)aralkyl group selected from benzyl, 1-phenylethyl,2-phenylethyl or phenylpropyl)

such as γ-butyrolactam, γ-butyrolactone, imidazolidinone orN-aminoimidazolidinone, or a six membered aromatic ring with one tothree N heteroatoms such as pyridyl, pyridazinyl, pyrazinyl,sym-triazinyl, unsym-triazinyl, pyrimidinyl or (C₁-C₃)alkylthiopyridazinyl, or a six membered saturated ring with one ortwo N, O, S or Se heteroatoms and an adjacent appended O heteroatom suchas 2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-2-dioxo-1-piperazinyl,2-dioxomorpholinyl, 2-dioxothiomorpholinyl; or --(CH₂)_(n) COOR⁴ wheren=0-4 and R⁴ is selected from hydrogen; straight or branched (C₁-C₃)alkyl selected from methyl, ethyl, n-propyl or 1-methylethyl; or (C₆-C10)aryl selected from phenyl, α-naphthyl or β-naphthyl; with theproviso that R² and R³ cannot both be hydrogen;

or R² and R³ taken together are --(CH₂)₂ B(CH₂)₂ --, wherein B isselected from (CH₂)_(n) and n=0-1, --NH, --N(C₁ -C₃)alkyl [straight orbranched], --N(C₁ -C₄)alkoxy, oxygen, sulfur or substituted congenersselected from (L or D)proline, ethyl (L or D) prolinate, morpholine,pyrrolidine or piperidine; and the pharmacologically acceptable organicand inorganic salts or metal complexes.

Particularly preferred compounds are compounds according to the aboveformula I and II wherein:

R is selected from hydrogen; straight or branched (C₁ -C₈)alkyl groupselected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,hexyl, heptyl and octyl; α-mercapto(C₁ -C₄)alkyl group selected frommercaptomethyl, α-mercaptoethyl, α-mercapto-1-methylethyl andα-mercaptopropyl; α-hydroxy-(C₁ -C₄)alkyl group selected fromhydroxymethyl, α-hydroxyethyl, α-hydroxy-1-methylethyl andα-hydroxypropyl; carboxyl(C₁ -C₈)alkyl group; (C₆ -C₁₀)aryl groupselected from phenyl, α-naphthyl and β-naphthyl; (C₇ -C₉)aralkyl groupselected from benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl; R¹is selected from hydrogen and (C₁ -C₆)alkyl selected from methyl, ethyl,propyl, isopropyl, butyl, isobutyl, pentyl and hexyl;

when R does not equal R¹ the stereochemistry of the asymmetric carbon(i.e. the carbon bearing the W substituent) maybe be either the racemate(DL) or the individual enantiomers (L or D);

W is selected from amino; (C₁ -C₁₂) straight or branched alkylmonosubstituted amino group substitution selected from methyl, ethyl,n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl,1,1-dimethylethyl, n-pentyl, 2-methylbutyl, 1,1-dimethylpropyl,2,2-dimethylpropyl, 3-methylbutyl, n-hexyl, 1-methylpentyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3-methylpentyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 1-methyl-1-ethylpropyl, heptyl, octyl, nonyl anddecyl and the diastereomers and enantiomers of said branched alkylmonosubstituted amino group; (C₃ -C₈)cycloalkyl monosubstituted aminogroup substitution selected from cyclopropyl,trans-1,2-dimethylcyclopropyl, cis-1,2-dimethylcyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and thediastereomers and enantiomers of said (C₃ -C₈)cycloalkyl monosubstitutedamino group; [(C₄ -C₁₀)cycloalkyl]alkyl monosubstituted amino groupsubstitution selected from (cyclopropyl)methyl, (cyclopropyl)ethyl and(cyclobutyl)methyl; (C₃ -C₁₀)alkenyl monosubstituted amino groupsubstitution selected from allyl, 3-butenyl, 2-butenyl (cis or trans),2-pentenyl, 4-octenyl, 2,3-dimethyl-2-butenyl, 3-methyl-2-butenyl2-cyclopentenyl and 2-cyclohexenyl; (C₇ -C₁₀)aralkylamino groupsubstitution selected from benzyl, 2-phenylethyl, 1-phenylethyl,2-(naphthyl)methyl, 1-(naphthyl)methyl and phenylpropyl; straight orbranched symmetrical disubstituted (C₂ -C₁₄)alkylamino groupsubstitution selected from dimethyl, diethyl, diisopropyl anddi-n-propyl; straight or branched unsymmetrical disubstituted (C₃-C₁₄)alkylamino group wherein the total number of carbons in thesubstitution is not more than 14; unsymmetrical disubstituted (C₄-C₁₄)cycloalkylamino group wherein the total number of carbons in thesubstitution is not more than 14; (C₂ -C₈)azacycloalkyl and substituted(C₂ -C₈)azacycloalkyl group selected from aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, 4-methylpiperidinyl, 2-methylpyrrolidinyl,cis-3,4-dimethylpyrrolidinyl, and trans-3,4-dimethylpyrrolidinyl and thediastereomers and enantiomers of said (C₂ -C₈)azacycloalkyl andsubstituted (C₂ -C₈)aza- cycloalkyl group; 1-azaoxacycloalkyl groupselected from morpholinyl and 1-aza-5-oxacycloheptane; substituted1-azaoxacycloalkyl group selected from 2-(C₁ -C₃)alkylmorpholinyl, 3-(C₁-C₃)alkylisooxazolidinyl and tetrahydrooxazinyl; [1,n]-diazacycloalkyland substituted [1,n]-diazacycloalkyl group selected from piperazinyl,2-(C₁ -C₃)alkylpiperazinyl, 4-(C₁ -C₃)alkylpiperazinyl,2,4-dimethylpiperazinyl, 4-hydroxypiperazinyl,2,5-diazabicyclo[2.2.1]hept-2-yl,2,5-diaza-5-methylbicyclo[2.2.1]hept-2-yl, and2,3-diaza-3-methylbicyclo[2.2.2]oct-2-yl, the diastereomers orenantiomers of said [1,n]-diazacycloalkyl and substituted[1,n]-diazacycloalkyl group; 1-azathiacycloalkyl and substituted1-azathiacycloalkyl group selected from thiomorpholinyl and 2-(C₁-C₃)alkylthiomorpholinyl; N-azolyl and substituted N-azolyl groupselected from 1-imidazolyl, 2-(C₁ -C₃)alkyl-1-imidazolyl, 3-(C₁-C₃)alkyl-1-imidazolyl, 1-pyrrolyl, 2-(C₁ -C₃)alkyl-1-pyrrolyl, 3-(C₁-C₃)alkyl-1-pyrrolyl, 1-pyrazolyl, 3-(C₁ -C₃)alkyl-1-pyrazolyl, indolyl,1-(1,2,3-triazolyl), 4-(C₁ -C₃)alkyl-1-(1,2,3-triazolyl), 5-(C₁-C₃)alkyl-1-(1,2,3-triazolyl) and 4-(1,2,4-triazolyl;(heterocycle)methylamino group selected from 2- or 3-furylmethylamino,2- or 3-thienylmethylamino, 2-, 3- or 4-pyridylmethylamino, 2- or5-pyridazinylmethylamino, 2-pyrazinylmethylamino,2-(imidazolyl)methylamino, (benzimidazolyl)methylamino, and(benzothiazolyl)methylamino and substituted (heterocycle)methylaminogroup (substitution selected from straight or branched (C₁ -C₆)alkyl);carboxy(C₂ -C₄)alkylamino group selected from aminoacetic acid,α-aminopropionic acid, β-aminopropionic acid, α-butyric acid, andβ-aminobutyric acid and the enantiomers of said carboxy(C₂-C₄)alkylamino group; (C₁ -C₄)alkoxycarbonylamino group substitutionselected from methoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl,propoxycarbonyl, isoproproxycarbonyl, 1,1-dimethylethoxycarbonyl,n-butoxycarbonyl, and 2-methylpropoxycarbonyl; (C₁ -C₄)alkoxyamino groupsubstitution selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy,n-butoxy, 2-methylpropoxy, and 1,1-dimethylethoxy; (C₇-C₁₁)arylalkoxyamino group substitution selected from benzyoxy,2-phenylethoxy, 1-phenylethoxy, 2-(naphthyl)methoxy, 1-(naphthyl)methoxyand phenylpropoxy;

R² is selected from hydrogen; straight or branched (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl; (C₆ -C₁₀)arylgroup selected from phenyl, α-naphthyl or β-naphthyl; (C₇ -C₉)aralkylgroup selected from benzyl, 1-phenylethyl, 2-phenylethyl orphenylpropyl; a heterocycle group selected from a five membered aromaticor saturated ring with one N, O, S or Se heteroatom optionally having abenzo or pyrido ring fused thereto: ##STR15## such as pyrrolyl,N-methylindolyl, indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl, thienyl,benzothienyl or selenazolyl, or a five membered aromatic ring with twoN, O, S or Se heteroatoms optionally having a benzo or pyrido ring fusedthereto: ##STR16## such as imidazolyl, pyrazolyl, benzimidazolyl,oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl,3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl, or a fivemembered saturated ring with one or two N, O, S or Se heteroatoms and anadjacent appended O heteroatom: ##STR17## (A is selected from hydrogen;straight or branched (C₁ -C₄)alkyl; C₆ -aryl; substituted C₆ -aryl(substitution selected from halo, (C₁ -C₄)alkoxy, trihalo(C₁ -C₃)alkyl,nitro, amino, cyano, (C₁ -C₄)alkoxycarbonyl, (C₁ -C₃)alkylamino orcarboxy); (C₇ -C₉)aralkyl group selected from benzyl, 1-phenylethyl,2-phenylethyl or phenylpropyl)

such as γ-butyrolactam, γ-butyrolactone, imidazolidinone orN-aminoimidazolidinone, or a six membered aromatic ring with one tothree N heteroatoms such as pyridyl, pyridazinyl, pyrazinyl,sym-triazinyl, unsym-triazinyl, pyrimidinyl or (C₁ -C₃)alkylthiopyridazinyl, or a six membered saturated ring with one or twoN, O, S or Se heteroatoms and an adjacent appended O heteroatom such as2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-2-dioxo-1-piperazinyl,2-dioxomorpholinyl, 2-dioxothiomorpholinyl; or --(CH₂)_(n) COOR⁴ wheren=0-4 and R⁴ is selected from hydrogen; straight or branched (C₁-C₃)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl;or (C₆ -C₁₀)aryl group selected from phenyl, α-naphthyl, β-naphthyl; R³is selected from hydrogen; straight or branched (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl; (C₆ -C₁₀)arylgroup selected from phenyl, α-naphthyl or γ-naphthyl; (C₇ -C₉)aralkylgroup such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; aheterocycle group selected from a five membered aromatic or saturatedring with one N, O, S or Se heteroatom optionally having a benzo orpyrido ring fused thereto: ##STR18## such as pyrrolyl, N-methylindolyl,indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl, thienyl,benzothienyl or selenazolyl, or a five membered aromatic ring with twoN, O, S or Se heteroatoms optionally having a benzo or pyrido ring fusedthereto: ##STR19## such as imidazolyl, pyrazolyl, benzimidazolyl,oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl,3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl, or a fivemembered saturated ring with one or two N, O, S or Se heteroatoms and anadjacent appended O heteroatom: ##STR20## (A is selected from hydrogen;straight or branched (C₁ -C₄)alkyl; C₆ -aryl; substituted C₆ -aryl(substitution selected from halo, (C₁ -C₄)alkoxy, trihalo(C₁ -C₃)alkyl,nitro, amino, cyano, (C₁ -C₄)alkoxycarbonyl, (C₁ -C₃)alkylamino orcarboxy); (C₇ -C₉)aralkyl group selected from benzyl, 1-phenylethyl,2-phenylethyl or phenylpropyl)

such as γ-butyrolactam, γ-butyrolactone, imidazolidinone orN-aminoimidazolidinone, or a six membered aromatic ring with one tothree N heteroatoms such as pyridyl, pyridazinyl, pyrazinyl,sym-triazinyl, unsym-triazinyl, pyrimidinyl or (C₁-C₃)alkylthiopyridazinyl, or a six membered saturated ring with one ortwo N, O, S or Se heteroatoms and an adjacent appended O heteroatom suchas 2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-2-dioxo-1-piperazinyl,2-dioxomorpholinyl, 2-dioxo-thiomorpholinyl; or --(CH₂)_(n) COOR⁴ wheren=0-4 and R⁴ is selected from hydrogen; straight or branched (C₁-C₃)alkyl selected from methyl, ethyl, n-propyl or 1-methylethyl; or (C₆-C₁₀)aryl selected from phenyl, α-naphthyl or γ-naphthyl; with theproviso that R² and R³ cannot both be hydrogen;

or R² and R³ taken together are --(CH₂)₂ B(CH₂)₂ --, wherein B isselected from (CH₂)_(n) and n=0-1, --NH, --N(C₁ -C₃)alkyl [straight orbranched], --N(C₁ -C₄)alkoxy, oxygen, sulfur or substituted congenersselected from (L or D)proline, ethyl(L or D)prolinate, morpholine,pyrrolidine or piperidine; and the pharmacologically acceptable organicand inorganic salts or metal complexes.

Compounds of special interest are compounds according to the aboveformula I and II wherein:

R is selected from hydrogen; straight or branched (C₁ -C₂)alkyl groupselected from methyl and ethyl;

R¹ selected from hydrogen or (C₁ -C₂)alkyl selected from methyl andethyl;

when R does not equal R¹ the stereochemistry of the asymmetric carbon(i.e. the carbon bearing the W substituent) maybe be either the racemate(DL) or the individual enantiomers (L or D);

W is selected from amino; (C₁ -C₈) straight or branched alkylmonosubstituted amino group substitution selected from methyl, ethyl,n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl,n-hexyl and n-octyl; (C₃ -C₆)cycloalkyl monosubstituted amino groupsubstitution selected from cyclopropyl, cyclopentyl and cyclohexyl; [(C₄-C₅)cycloalkyl]alkyl monosubstituted amino group substitution selectedfrom (cyclopropyl)methyl and (cyclopropyl)ethyl; (C₃ -C₄)alkenylmonosubstituted amino group substitution selected from allyl and3-butenyl; (C₇ -C₁₀)aralkylamino group substitution selected frombenzyl, 2-phenylethyl and 1-phenylethyl; straight or branchedsymmetrical disubstituted (C₂ -C₄)alkylamino group substitution selectedfrom dimethyl and diethyl; straight or branched unsymmetricaldisubstituted (C₃)alkylamino group substitution selected frommethyl(ethyl); (C₂ -C₅)azacycloalkyl group selected from pyrrolidinyland piperidinyl; 1-azaoxacycloalkyl group selected from morpholinyl;substituted 1-azaoxacycloalkyl group selected from 2-(C₁-C₃)alkylmorpholinyl; [1,n]-diazacycloalkyl and substituted[1,n]-diazacycloalkyl group selected from piperazinyl, 2-(C₁-C₃)alkylpiperazinyl, 4-(C₁ -C₃)alkylpiperazinyl, and2,5-diaza-5-methylbicyclo[2.2.1]hept-2-yl and the diastereomers andenantiomers of said [1,n]-diazacycloalkyl and substituted[1,n]-diazacycloalkyl group; 1-azathiacycloalkyl and substituted1-azathiacycloalkyl group selected from thiomorpholinyl and 2-(C₁-C₃)alkylthiomorpholinyl; N-azolyl group selected from 1-imidazolyl;(heterocycle)methylamino group selected from 2- or 3-thienylmethylaminoand 2-, 3- or 4-pyridylmethylamino; (C₁ -C₄)alkoxycarbonylamino groupsubstitution selected from methoxycarbonyl, ethoxycarbonyl, and1,1-dimethylethoxycarbonyl;

R² is selected from hydrogen; straight or branched (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl;

R³ is selected from hydrogen; straight or branched (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl; with the provisothat R² and R³ cannot both be hydrogen;

or R² and R³ taken together are --(CH₂)₂ B(CH₂)₂ --, wherein B isselected from (CH₂)_(n) and n=0-1, --NH, --N(C₁ -C₃)alkyl [straight orbranched], --N(C₁ -C₄)alkoxy, oxygen, sulfur or substituted congenersselected from (L or D)proline, ethyl(L or D)prolinate, morpholine,pyrrolidine or piperidine; and the pharmacologically acceptable organicand inorganic salts or metal complexes.

Also included in the present invention are compounds useful asintermediates for producing the above compounds of formula I and II.Such intermediate include those having the formula III: ##STR21##wherein: Y is selected from (CH₂)_(n) X, n=0-5, X is halogen selectedfrom bromine, chlorine, fluorine and iodine;

R is selected from hydrogen; straight or branched (C₁ -C₈)alkyl groupselected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,hexyl, heptyl and octyl; α-mercapto(C₁ -C₄)alkyl group selected frommercaptomethyl, α-mercaptoethyl, α-mercapto-1-methylethyl,α-mercaptopropyl and α-mercaptobutyl; α-hydroxy(C₁ -C₄)alkyl groupselected from hydroxymethyl, α-hydroxyethyl, α-hydroxy-1-methylethyl,α-hydroxypropyl and α-hydroxybutyl; carboxyl(C₁ -C₈)alkyl group; (C₆-C₁₀)aryl group selected from phenyl, α-naphthyl and β-naphthyl;substituted(C₆ -C₁₀)aryl group (substitution selected from hydroxy,halogen, (C₁ -C₄)alkoxy, trihalo(C₁ -C₃)alkyl, nitro, amino, cyano, (C₁-C₄)alkoxycarbonyl, (C₁ -C₃)alkylamino and carboxy); (C₇ -C₉)aralkylgroup selected from benzyl, 1-phenylethyl, 2-phenylethyl andphenylpropyl; substituted(C₇ -C₉)aralkyl group [substitution selectedfrom halo, (C₁ -C₄)alkyl, nitro, hydroxy, amino, mono- or di-substituted(C₁ -C₄)alkylamino, (C₁ -C₄)alkoxy, (C₁ -C₄)alkylsulfonyl, cyano andcarboxy];

R¹ is selected from hydrogen and (C₁ -C₆)alkyl selected from methyl,ethyl propyl, isopropyl, butyl, isobutyl, pentyl and hexyl;

when R does not equal R¹ the stereochemistry of the asymmetric carbon(i.e. the carbon bearing the W substituent) maybe be either the racemate(DL) or the individual enantiomers (L or D); and the pharmacologicallyacceptable organic and inorganic salts and metal complexes.

Preferred compounds are compounds according to the above formula IIIwherein:

Y is selected from (CH₂)_(n) X, n=0-5, X is halogen selected frombromine, chlorine, fluorine and iodine;

R is selected from hydrogen; straight or branched (C₁ -₈)alkyl groupselected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,hexyl, heptyl and octyl; α-mercapto(C₁ -C₄)alkyl group selected frommercaptomethyl, α-mercaptoethyl, α-mercapto-1-methylethyl,α-mercaptopropyl and α-mercaptobutyl; α-hydroxy(C₁ -C₄)alkyl groupselected from hydroxymethyl, α-hydroxyethyl, α-hydroxy-1-methylethyl,α-hydroxypropyl and α-hydroxybutyl; carboxyl(C₁ -C₈)alkyl group; (C₆-C₁₀)aryl group selected from phenyl, α-naphthyl and γ-naphthyl; (C₇-C₉)aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl andphenylpropyl; substituted(C₇ -C₉)aralkyl group [substitution selectedfrom halo, (C₁ -C₄)alkyl, nitro, hydroxy, amino, mono- or di-substituted(C₁ -C₄)alkylamino, (C₁ -C₄)alkoxy, (C₁ -C₄)alkylsulfonyl, cyano andcarboxy];

R¹ is selected from hydrogen and (C₁ -C₆)alkyl selected from methyl,ethyl propyl, isopropyl, butyl, isobutyl, pentyl and hexyl;

when R does not equal R¹ the stereochemistry of the asymmetric carbon(i.e. the carbon bearing the W substituent) maybe be either the racemate(DL) or the individual enantiomers (L or D); and the pharmacologicallyacceptable organic and inorganic salts and metal complexes.

Particularly preferred compounds are compounds according to the aboveformula III wherein:

Y is selected from (CH₂)_(n) X, n=0-5, X is halogen selected frombromine, chlorine, fluorine and iodine;

R is selected from hydrogen; straight or branched (C₁ -C₈)alkyl groupselected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,hexyl, heptyl and octyl; α-mercapto(C₁ -C₄)alkyl group selected frommercaptomethyl, α-mercaptoethyl, α-mercapto-1-methylethyl andα-mercaptopropyl; α-hydroxy(C₁ -C₄)alkyl group selected fromhydroxymethyl, α-hydroxyethyl, α-hydroxy-1-methylethyl andα-hydroxypropyl; carboxyl(C₁ -C₈)alkyl group; (C₆ -C₁₀)aryl groupselected from phenyl, α-naphthyl and γ-naphthyl; (C₇ -C₉)aralkyl groupselected from benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl; R¹is selected from hydrogen and (C₁ -C₆)alkyl selected from methyl, ethyl,propyl, isopropyl, butyl, isobutyl, pentyl and hexyl;

when R does not equal R¹ the stereochemistry of the asymmetric carbon(i.e. the carbon bearing the W substituent) maybe be either the racemate(DL) or the individual enantiomers (L or D); and the pharmacologicallyacceptable organic and inorganic salts and metal complexes.

Compounds of special interest are compounds according to the aboveformula III wherein:

Y is selected from (CH₂)_(n) X, n=0-5, X is halogen selected frombromine, chlorine, fluorine and iodine;

R is selected from hydrogen; straight or branched (C₁ -C₂)alkyl groupselected from methyl and ethyl; R¹ is selected from hydrogen and (C₁-C₂)alkyl selected from methyl and ethyl; when R does not equal R¹ thestereochemistry of the asymmetric carbon (i.e. the carbon bearing the Wsubstituent) maybe be either the racemate (DL) or the individualenantiomers (L or D); and the pharmacologically acceptable organic andinorganic salts and metal complexes.

DESCRIPTION OF THE PREFERRED EMBODIMENTS.

The novel compounds of the present invention may be readily prepared inaccordance with the following schemes. ##STR22##

The 9-[(substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines, ormineral acid salts, can be made by the procedure described in scheme I.In accordance with scheme I, 9-amino-6-demethyl-6-deoxytetracycline orits mineral acid salt, 1, is dissolved in a mixture of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone and acetonitrile.Sodium carbonate is added and the mixture is stirred for 5 minutes. Anacid chloride of the formula: ##STR23## wherein R, R¹, W and X have beendescribed hereinabove is added and the reaction is stirred at roomtemperature for from 0.5-2 hours to give the corresponding9-[(substituted glycyl)amido]-6-demethyl-6-deoxytetracycline, or itsmineral acid salt 3. ##STR24##

The preferred method for producing 9-[(substitutedglycyl)amido]-6-demethyl-6-deoxytetracyclines or its mineral acid salt3, is shown in scheme II. This method uses common intermediates whichare easily prepared by reacting commercially available haloacyl halidesof the formula: ##STR25## wherein Y, R and R¹ are as defined hereinaboveand Q is halogen selected from bromine, chlorine, iodine and fluorine;with 9-amino-6-demethyl-6-deoxytetracyclines, or its mineral acid salt1, to give straight or branched9-[(haloacyl)amido]-6-demethyl-6-deoxytetracyclines or its mineral acidsalt, 2, in almost quantitative yield. The above intermediates, straightor branched 9-[(haloacyl)amido]-6-demethyl-6-deoxytetracyclines or itsmineral acid salt 2, react with a wide variety of nucleophiles,especially amines, having the formula WH, wherein W is as definedhereinabove to give the new 9-[(substitutedglycyl)amido]-6-demethyl-6-deoxytetracyclines or mineral acid salt 3 ofthe present invention.

In accordance with Scheme II, 9-amino-6-demethyl-6-deoxytetracycline orits mineral acid salt, 1, is mixed with

a) a polar-aprotic solvent such as1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidone, herein after calledDMPU, hexamethylphosphoramide herein after called HMPA,dimethylformamide, dimethylacetamide, N-methylpyrrolidone,1,2-dimethoxyethane or equivalent thereof;

b) an inert solvent such as acetonitrile, methylene chloride,tetrahydrofuran chloroform, carbon tetrachloride, 1,2-dichloroethane,tetrachloroethane, diethyl ether, t-butyl methylether, isopropyl etheror equivalent thereof;

c) a base such as sodium carbonate, sodium bicarbonate, sodium acetate,potassium carbonate, potassium bicarbonate, triethylamine, cesiumcarbonate, lithium carbonate or bicarbonate equivalents; and

d) a straight or branched haloacyl halide of the formula: ##STR26##wherein Y, R, R¹ and Q are as defined hereinabove such as bromoacetylbromide, chloroacetyl chloride or 2-bromopropionyl bromide or equivalentthereof; the halo, Y, and halide, Q, in the haloacyl halide can be thesame or different halogen and is selected from bromine, chlorine, iodineand fluorine; Y is (CH₂)_(n) X, n=0-5, X is halogen;

e) for 0.5 to 5 hours at room temperature to the reflux temperature ofthe reaction; to form the corresponding9-[(haloacyl)amido]-6-de-methyl-6-deoxytetracycline, 2, or its mineralacid salt.

The intermediate, 9-[(haloacyl)amido]-6-de-methyl-6-deoxytetracycline ormineral acid salt 2, is treated, under an inert atmosphere of helium,argon or nitrogen, with

a) a nucleophile WH such as an amine or substituted amine or equivalentfor example methylamine, dimethylamine, ethylamine, n-butylamine,propylamine or n-hexylamine;

b) a polar-aprotic solvent such as DMPU, HMPA dimethylformamide,dimethylacetamide, N-methylpyrrolidone or 1,2-dimethoxyethane;

c) for from 0.5-2 hours at room temperature or under reflux temperatureto produce the desired 9-[(substitutedglycyl)amido]-6-demethyl-6-deoxytetracycline, 3, or its mineral acidsalt. ##STR27##

In accordance with Scheme III, compounds of formula 3 are N-alkylated inthe presence of formaldehyde and either a primary amine such asmethylamine, ethylamine, benzylamine, methyl glycinate, (L or D)alanine,(L or D)lysine or their substituted congeners; or a secondary amine suchas morpholine, pyrrolidine, piperidine or their substituted congeners togive the corresponding Mannich base adduct, 4.

The 9-[(substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines may beobtained as metal complexes such as aluminum, calcium, iron, magnesium,manganese and complex salts; inorganic and organic salts andcorresponding Mannich base adducts using methods known to those skilledin the art (Richard C. Larock, Comprehensive Organic Transformations,VCH Publishers, 411-415, 1989). It is well known to one skilled in theart that an appropriate salt form is chosen based on physical andchemical stability, flowability, hygroscopicity and solubility.Preferably, the 9-[(substitutedglycyl)amido]-6-demethyl-6-deoxytetracyclines are obtained as inorganicsalt such as hydrochloric, hydrobromic, hydroiodic, phosphoric, nitricor sulfate; or organic salt such as acetate, benzoate, citrate, cysteineor other amino acids, fumarate, glycolate, maleate, succinate, tartrate,alkylsulfonate or arylsulfonate. Depending on the stochiometry of theacids used, the salt formation occurs with the C(4)-dimethylamino group(1 equivalent of acid) or with both the C(4)-dimethylamino group and theW group (2 equivalents of acid). The salts are preferred for oral andparenteral administration.

Some of the compounds of the hereinbefore described Schemes have centersof asymmetry at the carbon bearing the W substituent. The compounds may,therefore, exist in at least two (2) stereoisomeric forms. The presentinvention encompasses the racemic mixture of stereo isomers as well asall stereoisomers of the compounds whether free from other stereoisomersor admixed with stereoisomers in any proportion of enantiomers. Theabsolute configuration of any compound may be determined by conventionalX-ray crystallography.

The stereochemistry centers on the tetracycline unit (i.e. C-4, C-4a,C-5a and C-12a) remain intact throughout the reaction sequences.

BIOLOGICAL ACTIVITY Method for in Vitro Antibacterial Evaluation (TablesI, II and V)

The minimum inhibitory concentration (MIC), the lowest concentration ofthe antibiotic which inhibits growth to the test organism, is determinedby the agar dilution method using Muller-Hinton II agar (BaltimoreBiological Laboratories.). An inoculum density of 1-5×10⁵ CFU/ml and arange of antibiotic concentrations (32-0.004 μg/ml) is used. The platesare incubated for 18 hours at 35° C. in a forced air incubator. The testorganisms comprise strains that are sensitive to tetracycline andgenetically defined strains that are resistant to tetracycline, due toinability to bind to bacterial ribosomes (tetM) or by a tetK encodedmembrane protein which confers tetracycline resistance byenergy-dependent efflux of the antibiotic from the cell.

E. coli in Vitro Protein Translation System (Table III)

An in vitro, cell free, protein translation system using extracts fromE. coli strain MRE600 (tetracycline sensitive) and a derivative ofMRE600 containing the tetM determinant has been developed based onliterature methods [J. M. Pratt, Coupled Transcription-translation inProkaryotic Cell-free Systems, Transcription and Translation, aPractical Approach, (B. D. Hames and S. J. Higgins, eds) p. 179-209, IRLPress, Oxford-Washington, 1984].

Using the system described above, the tetracycline compounds of thepresent invention are tested for their ability to inhibit proteinsysnthesis in vitro. Briefly, each 10 μl reaction contains S30 extract(a whole extract) made from either tetracycline sensitive cells or anisogenic tetracycline resistant (tetM) strain, low molecular weightcomponents necessary for transcription and translation (i.e. ATP andGTP), a mix of 19 amino acids (no methionine), ³⁵ S labeled methionine,DNA template (either pBR322 or pUC119), and either DMSO (control) or thenovel tetracycline compound to be tested ("novel TC") dissolved in DMSO.

The reactions are incubated for 30 minutes at 37° C. Timing is initiatedwith the addition of the S30 extract, the last component to be added.After 30 minutes, 2.5 μl of the reaction is removed and mixed with 0.5ml of 1N NaOH to destroy RNA and tRNA. Two ml of 25% trichloroaceticacid is added and the mixture incubated at room temperature for 15minutes. The trichloroacetic acid precipitated material is collected onWhatman GF/C filters and washed with a solution of 10% trichloroaceticacid. The filters are dried and the retained radioactivity, representingincorporation of ³⁵ S-methionine into polypeptides, is counted usingstandard liquid scintillation methods.

The percent inhibition (P.I.) of protein synthesis is determined to be:##EQU1##

In Vivo Antibacterial Evaluation (Table IV)

The therapeutic effects of tetracyclines are determined against an acutelethal infection with Staphylococcus aureus strain Smith (tetracyclinesensitive). Female, mice, strain CD-1 (Charles River Laboratories), 20±2grams, are challenged by an intraperitoneal injection of sufficientbacteria (suspended in hog mucin) to kill non-treated controls within24-48 hours. Antibacterial agents, contained in 0.5 ml of 0.2% aqueousagar, are administered subcutaneously or orally 30 minutes afterinfection. When an oral dosing schedule is used, animals are deprived offood for-5 hours before and 2 hours after infection. Five mice aretreated at each dose level. The 7 day survival ratios from 3 separatetests are pooled for calculation of median effective dose (ED₅₀).

Testing Results

The claimed compounds exhibit antibacterial activity against a spectrumof tetracycline sensitive and resistant Gram-positive and Gram-negativebacteria, especially, strains of E. coli and S. aureus containing tetMresistance determinants, and E. coli containing the tetA, tetB, tetC andtetD resistance determinants. Notable is9-[(N,N-dimethylglycyl)amido]-6-demethyl-6-deoxytetracycline, CC, asshown in Table I, which demonstrated excellent in vitro activity againsttetracycline resistant strains containing the tetM resistancedeterminant (such as S. aureus UBMS 88-5, S. aureus UBMS 90-1 and 90-2,E. coli UBMS 89-1 and 90-4) and tetracycline resistant strainscontaining tetB resistance determinants (such as E. coli UBMS 88-1 andE. coli TN10C tetB).9-[(N,N-dimethylglycyl)amido]-6-demethyl-6-deoxytetracycline, also hasgood activity against E. coli strains containing tetA, tetC and tetDresistance determinants. It is as effective as minocycline againstsusceptible strains and is superior to minocycline against a number ofrecently isolated bacteria from clinical sources. (Table II)

As shown in Table II, the free base, disulfate, dihydrochloride,monohydrochloride and the Mannich bases of9-[(N,N-dimethylglycyl)amindo]-6-de-methyl-6-deoxytetracycline, showcomparable in vitro antibacterial activity.

Minocycline and9-[(N,N-dimethylglycyl)amido]-6-demethyl-6-deoxytetracycline are assayedfor their ability to inhibit protein synthesis taking place on eitherwild type or TetM modified ribosomes using a coupled transcription andtranslation system. Both compounds effectively inhibit protein synthesisoccurring on wild type ribosomes, at equivalent levels of activity.Minocycline is not effective in inhibiting protein synthesis occurringon tetM modified ribosomes. In contrast,9-[(N,N-dimethylglycyl)amido]-6-demethyl-6-deoxytetracycline iseffective at inhibiting protein synthesis occuring on TetM modifiedribosomes, although a slightly higher concen-tration is required toachieve similar levels of inhibition relative to wild type ribosomes.(Table III)

9-[(N,N-Dimethylglycyl)amido]-6-demethyl-6-deoxytetracycline bindsreversibly to its target (the ribosome) since bacterial growth resumeswhen the compound is removed by washing of the organism. Therefore, theability of 9-[(N,N-dimethylglycyl)amido]-6-demethyl-6-deoxytetracyclineto inhibit bacterial growth appears to be a direct consequence of itsability to inhibit protein synthesis at the ribosome level.

As shown in Table IV, the claimed compounds AA, BB, DD, CC, H, C, D, Gand Q show very good in vivo activity when tested intraveneously againstthe minocycline sensitive organism, S. aureus Smith. The claimedcompound CC when administered intraveneously exhibits potent activity(ED₅₀ 1.6 mg/kg) against E. coli UBMS 90-4 (TetM), which is resistant tominocycline, i.e. (ED₅₀ >32 mg/kg).

As shown in Table V,9-[(N,N-dimethylglycyl)amido)]-6-demethyl-6-deoxytetracycline showspotent in vitro antibacterial activity against a broad spectrum ofrecent clinical isolates, including a number from veterinary sources. Itwas more active than minocycline and tetracycline against the majorityof the isolates tested. The claimed compound is especially activeagainst E. faecalis, E. faecium including vancomycin resistant strains.The 9-[(dimethylglycyl)amido]-6-demethyl-6-deoxytetracycline alsoexhibits potent activity against E. coli, Salmonella spp., Shigellaspp., Salmonella choleraesuis, Proteus mirabilis, Proteus vulgaris,Morganella morganii, Neisseria gonorrhoeae, Bacteroides spp.,Clastridium spp. and Streptococcus spp. The activity of the9-[(N,N-dimethylglycyl)amido]-6-demethyl-6-deoxytetracycline isgenerally greater than minocycline and tetracycline.

As can be seen from Tables I-V, compounds of the invention can be usedto prevent or control important mammalian and veterinary diseases suchas diarrhea, urinary tract infections, infections of skin and skinstructure, ear, nose and throat infections, wound infections, mastitisand the like.

Thus, the improved efficacy of9-[(N,N-dimethylglycyl)amido]-6-demethyl-6-deoxytetracycline isdemonstrated by the in vitro activity against isogenic strains intowhich the resistance determinants, such as tetM, are cloned (Table I);the inhibition of protein synthesis by TetM modified ribosomes (TableIII); and the in vivo activity against experimental infections caused bystrains resistant to the tetracyclines, due to the presence ofresistance determinants, such as tet M (Table IV).

When the compounds are employed as antibacterials, they can be combinedwith one or more pharmaceutically acceptable carriers, for example,solvents, diluents and the like, and may be administered orally in suchforms as tablets, capsules, dispersible powders, granules, orsuspensions containing, for example, from about 0.05 to 5% of suspendingagent, syrups containing, for example, from about 10 to 50% of sugar,and elixirs containing for example, from about 20 to 50% ethanol and thelike, or parenterally in the form of sterile injectable solutions orsuspensions containing from about 0.05 to 5% suspending agent in anisotonic medium. Such pharmaceutical preparations may contain, forexample, from about 25 to about 90% of the active ingredient incombination with the carrier, more usually between about 5% and 60% byweight.

An effective amount of compound from 2.0 mg/kg of body weight to 100.0mg/kg of body weight should be administered one to five times per dayvia any typical route of administration including but not limited tooral, parenteral (including subcutaneous, intravenous, intramuscular,intrasternal injection or infusion techniques), topical or rectal, indosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. It will beunderstood, however, that the specific dose level and frequency ofdosage for any particular patient may be varied and will depend upon avariety of factors including the activity of the specific compoundemployed, the metabolic stability and length of action of that compound,the age, body weight, general health, sex, diet, mode and time ofadministration, rate of excretion, drug combination, the severity of theparticular condition, and the host undergoing therapy.

These active compounds may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, non-ionic surfactants and edible oils suchas corn, peanut and sesame oils, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvants customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, for example,vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease ofpreparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inglycerol, liquid, polyethylene glycols and mixtures thereof in oils.Under ordinary conditions of storage and use, these preparations containa preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserve against thecontaminating action of micoorganisms such as bacterial and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oil.

The invention will be more fully described in conjunction with thefollowing specific examples which are not be construed as limiting thescope of the invention.

    ______________________________________    COMPOUND LEGEND FOR TABLES    ______________________________________    A        [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-             7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octa-             hydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-             naphthacenyl]-4-methyl-1-piperidineacetamide             dihydrochloride    B        [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-             [[2-(dimethylamino)-1-oxopropyl]amino]-1,4,             4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetra-             hydroxy-1,11-dioxo-2-naphthacenecarboxamide             dihydrochloride    C        [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,             4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetra-             hydroxy-1,11-dioxo-9-[[(propylamino)acetyl]-             amino]-2-naphthacenecarboxamide             dihydrochloride    D        [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-             7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octa-             hydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-             naphthacenyl]-1-pyrrolidineacetamide             dihydrochloride    E        [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-             [[(ethylamino)acetyl]amino)-1,4,4a,5,5a,6,11,             12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-             dioxo-2-naphthacenecarboxamide             dihydrochloride    F        [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,             4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetra-             hydroxy-9-[[(methylamino)acetyl]amino]-1,11-             dioxo-2-naphthacenecarboxamide             dihydrochloride    G        [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-             [[(hexylamino)acetyl]amino]-1,4,4a,5,5a,6,11,             12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-             dioxo-2-naphthacenecarboxamide             dihydrochloride    H        [4S-(4alpha,12aalpha)]-9-[[(Butylamino)-             acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,             6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-             1,11-dioxo-2-naphthacenecarboxamide             dihydrochloride    I        [7S-(7alpha,10aalpha)]-N-9-(Aminocarbonyl)-7-             (dimethylamino)-5,5a,6,6a,7,10,10a,12-octa-             hydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-1-             piperidineacetamide dihydrochloride (331,404)    J        [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,             4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetra-             hydroxy-1,11-dioxo-9-[[[(phenylmethyl)-             amino]acetyl]amino]-2-naphthacenecarboxamide             dihydrochloride    K        [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,             4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetra-             hydroxy-1,11-dioxo-9-[[[pentylamino)acetyl]-             amino]-2-naphthacenecarboxamide             monohydrochloride    L        [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,             4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetra-             hydroxy-1,11-dioxo-9-[[[(2-thienylmethyl)-             amino]acetyl)amino]-2-naphthacenecarboxamide             dihydrochloride    M        [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,             4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetra-             hydroxy-9-[[[(2-methylpropyl)amino]acetyl]-             amino]-1,11-dioxo-2-naphthacenecarboxamide             dihydrochloride    N        [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,             4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetra-             hydroxy-1,11-dioxo-9-[[[(2-pyridinylmethyl]-             amino]acetyl]amino]-2-naphthacenecarboxamide             dihydrochloride    O        [4S-(4alpha,12aalpha)]-9-[[(Diethylamino)-             acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,             6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-             1,11-dioxo-2-naphthacenecarboxamide             dihydrochloride    P        [7S-(7alpha,10aalpha)]-N-9-(Aminocarbonyl)-7-             (dimethylamino)-5,5a,6,6a,7,10,10a,12-octa-             hydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-             naphthacenyl]-α-methyl-1-pyrrolidinecar-             boxamide    Q        [4S-(4alpha,12aalpha)]-9-[[[(Cyclopropyl-             methyl)amino]acetyl]amino]-4-(dimethylamino)-             1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-             tetrahydroxy-1,11-dioxo-2-naphthacenecarbox-             amide dihydrochloride    R        [4S-(4alpha,12aalpha)]-9-[(Bromoacetyl)-             amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,             12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-             dioxo-2-naphthacenecarboxamide             monohydrochlorid    S        [4S-(4alpha,12aalpha)]-9-[(2-Bromo-1-oxopro-             pyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,             11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,             11-dioxo-2-naphthacenecarboxamide             dihydrochloride    T        Tetracycline    U        Minocycline    AA       [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-             [[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,             6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-             1,11-dioxo-2-naphthacenecarboxamide disulfate    BB       [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-             [[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,             6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-             1,11-dioxo-2-naphthacenecarboxamide    CC       [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-             [[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,             6,11,12a-octahydro-3,10,12,12a.-tetrahydroxy-             1,11-dioxo-2-naphthacenecarboxamide dihydro-             chloride    DD       [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-             [[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,             6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-             1,11-dioxo-2-naphthacenecarboxamide mono-             hydrochloride    EE       [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-             [[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,             6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-             1,11-dioxo-N-(1-pyrrolidinylmethyl)-2-             naphthacenecarboxamide    ______________________________________

                                      TABLE I    __________________________________________________________________________    ANTIBACTERIAL ACTIVITY OF 9-[(SUBSTITUTED GLYCYL)AMIDO]-6-DEMETHYL-6-DEOXY    TETRACYCLINES    MIC (μg/ml)    __________________________________________________________________________                   Compound    Organism       A     B   C   D   E   F    G   H    I   J   K    __________________________________________________________________________    E. coli UBMS 88-1 Tet B                   1     1   0.5 0.25                                     0.5 1    1   0.25 1   4   1    E. coli J3272 Tet sens                   NT    NT  NT  NT  NT  NT   NT  0.12 NT  NT  NT    E. coli MC 4100 Tet sens.                   0.25  0.25                             0.12                                 0.12                                     0.25                                         0.5  0.12                                                  NT   0.25                                                           0.5 0.5    E. coli PRP1 Tet A                   1     2   1   0.25                                     2   4    1   0.25 1   4   0.5    E. coli NC 4100 TNIOC Tet B                   1     0.5 0.5 0.25                                     1   1    1   0.25 1   4   0.5    E. coli J3272 Tet C                   1     1   0.5 0.25                                     1   4    1   0.12 1   4   0.5    E. coli UBMS 89-1 Tet M                   0.25  0.5 0.25                                 0.12                                     0.25                                         0.5  0.25                                                  0.12 0.25                                                           2   0.25    E. coli UBMS 89-2 Tet sens.                   0.5   1   0.25                                 0.25                                     0.5 1    1   0.12 0.5 4   0.25    E. coli J2175  0.5   1   0.25                                 0.25                                     0.5 0.5  1   0.25 0.5 4   0.5    E. coli BAJ9003 IMP MUT                   0.12  0.25                             0.06                                 0.06                                     0.12                                         0.5  0.12                                                  0.06 0.12                                                           0.5 0.25    E. coli UBMS 90-4 Tet M                   0.5   0.5 0.25                                 0.25                                     0.25                                         0.5  0.5 0.12 0.5 4   0.5    E. coli UBMS 90-5                   0.5   0.5 0.25                                 0.25                                     0.5 0.5  1   0.12 0.5 4   0.5    E. coli #311 (MP)                   0.25  0.5 0.5 0.25                                     0.5 0.5  1   0.12 0.5 4   0.5    E. coli ATCC 25922                   0.25  0.5 0.12                                 0.12                                     0.25                                         0.5  1   0.12 0.5 4   0.5    E. coli J3272 Tet D                   0.25  0.5 0.12                                 0.12                                     0.25                                         0.5  0.5 0.06 0.5 4   0.5    S. marcescens FPOR 8733                   8     8   4   2   4   4    8   2    8   >32 4    X. maltophilia NEMC 87210                   0.5   2   4   1   8   16   1   1    0.5 16  1    Ps. aeruginosa ATCC 27853                   >32   32  16  16  16  32   32  8    >32 >32 32    S. aureus NEMC 8769                   no growth                         0.06                             0.06                                 0.06                                     0.12                                         0.25 0.12                                                  0.03 0.5 1   0.12    S. aureus UBMS 88-4                   0.5   0.25                             0.25                                 0.12                                     0.5 0.5  0.25                                                  0.06 0.5 1   0.25    S. aureus UBMS 88-5 Tet M                   0.5   0.5 0.5 0.12                                     0.5 1    0.5 0.06 0.5 2   0.5    S. aureus USMS 88-7 Tet K                   1     1   2   0.5 8   16   1   1    0.5 4   2    S. aureus UBMS 90-1 Tet M                   1     0.5 0.25                                 0.25                                     0.5 0.5  1   0.12 0.5 4   0.5    S. aureus UBMS 90-3                   0.5   0.06                             0.06                                 0.12                                     0.12                                         0.5  0.25                                                  0.03 0.25                                                           0.5 0.25    S. aureus UBMS 90-2 Tet M                   0.5   0.25                             0.25                                 0.25                                     0.12                                         0.5  0.25                                                  0.12 0.25                                                           1   0.25    S. aureus IVES 2943                   0.5   1   4   1   16  >32  2   1    1   4   2    S. aureus ROSE (MP)                   2     4   16  2   >32 >32  4   4    4   8   8    S. aureus SMITH (MP)                   0.5   0.25                             0.12                                 0.12                                     0.25                                         0.5  0.25                                                  0.12 0.25                                                           0.5 0.25    S. aureus IVES 1 983                   1     1   4   1   8   16   1   2    1   4   2    S. aureus ATCC 29213                   0.5   0.25                             0.25                                 0.12                                     0.5 0.5  0.5 0.06 0.5 1   0.5    S. hemolyticus AVHAH 88-3                   2     1   0.5 0.25                                     1   1    2   0.5  2   4   2    Enterococcus 12201                   0.5   0.25                             0.25                                 0.12                                     0.25                                         0.5  0.25                                                  0.12 0.25                                                           2   0.25    E. faecalis ATCC 29212                   0.25  0.25                             0.12                                 0.12                                     0.25                                         0.5  0.12                                                  0.12 0.25                                                           0.25                                                               0.25    __________________________________________________________________________                   Compound    Organism       L    M   N    O   P    Q   R    S   T     U    __________________________________________________________________________    E. coli UBMS 88-1 Tet B                   32   1   >32  1   2    0.5 >32  >32 >32   16    E. coli J3272 Tet sens                   NT   NT  NT   NT  NT   NT  32   4   1     1    E. coli MC 4100 Tet sens.                   8    0.25                            8    0.5 0.25 0.25                                              NT   NT  0.25  0.12    E. coli PRP1 Tet A                   16   1   32   4   2    2   >32  >32 16    2    E. coli NC 4100 TNIOC Tet B                   32   1   32   1   2    1   >32  >32 >32   16    E. coli J3272 Tet C                   32   1   >32  1   1    0.5 >32  >32 >32   1    E. coli UBMS 89-1 Tet M                   8    0.5 16   0.5 0.5  0.5 8    >32 32    8    E. coli UBMS 89-2 Tet sens.                   16   1   32   1   1    1   32   16  1     1    E. coli J2175  16   1   >32  1   1    1   32   16  1     1    E. coli BAJ9003 IMP MUT                   4    0.25                            2    0.12                                     0.25 0.25                                              1    1   0.25  0.03    E. coli UBMS 90-4 Tet M                   8    0.5 16   0.5 1    0.25                                              32   >32 32    >32    E. coli UBMS 90-5                   16   1   32   1   0.5  0.5 32   8   0.5   1    E. coli #311 (MP)                   16   1   32   1   1    1   16   8   1     0.25    E. coli ATCC 25922                   8    0.5 32   0.5 1    0.5 16   8   0.5   0.25    E. coli J3272 Tet D                   16   0.25                            32   0.5 0.5  0.25                                              >32  >32 >32   8    S. marcescens FPOR 8733                   >32  8   >32  8   16   8   >32  >32 >32   4    X. maltophilia NEMC 87210                   >32  2   >32  1   4    4   16   16  8     0.12    Ps. aeruginosa ATCC 27853                   >32  32  >32  32  >32  16  >32  >32 8     8    S. aureus NEMC 8769                   8    8   8    1   0.5  0.5 0.25 0.25                                                       0.06  ≦0.015    S. aureus UBMS 88-4                   8    0.5 8    0.5 0.5  0.5 0.5  2   0.12  0.03    S. aureus UBMS 88-5 Tet M                   8    0.5 8    0.5 0.5  0.5 2    32  =32   4    S. aureus UBMS 88-7 Tet K                   16   2   >32  0.5 1    8   8    16  >32   0.06    S. aureus UBMS 90-1 Tet M                   8    0.5 8    0.5 0.5  0.5 1    32  >32   8    S. aureus UBMS 90-3                   4    0.25                            4    0.25                                     0.25 0.5 1    2   0.12  ≦0.015    S. aureus UBMS 90-2 Tet M                   8    0.5 8    0.5 0.5  0.5 2    16  32    2    S. aureus IVES 2943                   16   4   =32  1   2    8   16   32  >32   2    S. aureus ROSE (MP)                   32   8   >32  2   8    16  16   >32 >32   0.25    S. aureus SMITH (MP)                   4    0.5 4    0.25                                     0.5  0.5 1    1   0.12  0.03    S. aureus IVES 1983                   16   2   >32  0.5 1    4   16   32  >32   4    S. aureus ATCC 29213                   8    0.25                            8    0.5 0.5  0.5 1    2   ≦0.015                                                             ≦0.015    S. hemolyticus AVHAH 88-3                   8    2   >32  2   4    4   8    8   0.5   0.06    Enterococcus 12201                   8    0.5 8    0.25                                     0.25 0.5 4    32  32    8    E. faecalis ATCC 29212                   4    0.25                            4    0.25                                     0.25 0.25                                              2    16  16    2    __________________________________________________________________________

                                      TABLE II    __________________________________________________________________________    ANTIBACTERIAL ACTIVITY OF 9-[(SUBSTITUTED GLYCYL)AMIDO]-6-DEMETHYL-6-    DEOXYTETRACYCLINES MIC (μg/ml)                   Compound    Organism       AA   BB    CC    DD  EE  T    U    __________________________________________________________________________    E. coli UBMS 88-1 Tet B                   0.25 0.25  0.25  0.25                                        0.5 >32  16    E. coli J3272 Tet sens                   0.25 0.12  0.12  NT  NT  1    1    E. coli MC 4100 Tet sens.                   NT   NT    NT    0.06                                        0.12                                            0.25 0.12    E. coli PRP1 Tet A                   2    0.5   0.5   1   2   16   2    E. coli MC 4100 TNIOC Tet B                   0.25 0.25  0.25  0.25                                        0.5 >32  16    E. coli J3272 Tet C                   1    0.25  0.25  1   1   32   1    E. coli UBMS 89-1 Tet M                   0.25 0.12  0.12  0.5 0.25                                            32   8    E. coli UBMS 89-2 Tet sens.                   0.25 0.25  0.25  0.25                                        0.5 1    1    E. coli J2175  0.25 0.25  0.25  0.25                                        0.5 1    1    E. coli BAJ9003 IMP MUT                   0.06 no growth                              no growth                                    0.06                                        0.12                                            0.25 0.03    E. coli UBMS 90-4 Tet M                   0.25 0.12  0.12  0.12                                        0.25                                            32   >32    E. coli UBMS 90-5                   0.25 0.12  0.12  0.25                                        0.25                                            0.5  1    E. coli #311 (MP)                   0.50 0.12  0.12  0.25                                        0.5 1    0.25    E. coli ATCC 25922                   0.25 0.12  0.12  0.25                                        0.25                                            0.5  0.25    E. coli J3272 Tet D                   0.12 0.06  0.03  0.25                                        0.25                                            >32  8    S. marcescens FPOR 8733                   4    2     2     4   4   >32  4    X. maltophilia NEMC 87210                   2    1     1     2   2   8    0.12    Ps. aeruginosa ATCC 27853                   16   8     4     8   16  8    8    S. aureus NEMC 8769                   0.03 ≦0.015                              ≦0.015                                    0.03                                        0.25                                            0.06 ≦0.015    S. aureus UBMS 88-4                   0.12 0.06  0.03  0.12                                        0.25                                            0.12 0.03    S. aureus UBMS 88-5 Tet M                   0.12 0.12  0.03  0.12                                        0.25                                            >32  4    S. aureus UBMS 88-7 Tet K                   1    0.5   0.5   1   1   >32  0.06    S. aureus UBMS 90-1 Tet M                   0.25 0.12  0.06  0.12                                        0.25                                            >32  8    S. aureus UBMS 90-3                   0.06 0.06  0.03  0.06                                        0.12                                            0.12 ≦0.015    S. aureus UBMS 90-2 Tet M                   0.12 0.12  0.06  0.12                                        0.25                                            32   2    S. aureus IVES 2943                   1    0.5   0.5   1   2   >32  2    S. aureus ROSE (MP)                   4    2     1     4   8   >32  0.25    S. aureus SMITH (MP)                   0.12 0.06  0.03  0.12                                        0.25                                            0.12 0.03    S. aureus IVES 1983                   2    0.5   0.5   1   2   ≦32                                                 4    S. aureus ATCC 29213                   ≦0.015                        0.3   ≦0.015                                    0.12                                        0.25                                            ≦0.015                                                 ≦0.015    S. hemolyticus AVHAH 88-3                   0.5  0.12  0.12  0.25                                        0.5 0.5  0.06    Enterococcus 12201                   0.12 0.06  0.03  0.12                                        0.25                                            32   8    E. faecalis ATCC 29212                   0.12 0.06  0.03  0.06                                        0.12                                            16   2    __________________________________________________________________________     NT = not tested

                  TABLE III    ______________________________________    In Vitro Transcription and Translation    Sensitivity to 9-(Glycylamido)-6-deoxy-6-    demethyltetracycline Derivatives                    % Inhibition    Compound   Conc.     Wild Type S30 Tet M S30    ______________________________________    CC          1.0 mg/ml                         99            99               0.25 mg/ml                         98            94               0.06 mg/ml                         91            82    H           1.0 mg/mi                         99            98               0.25 mg/ml                         91            95               0.06 mg/ml                         86            72    U           1.0 mg/ml                         98            68               0.25 mg/ml                         89            43               0.06 mg/ml                         78             0    ______________________________________

                                      TABLE IV    __________________________________________________________________________    Effects of Glycylcycline Derivatives on Acute Lethal Infections in Mice    (ED.sub.50 mg/kg)            Route of            Antibiotic    Organism            Administration                    AA BB  DD CC H  C  D  G  Q  U    __________________________________________________________________________    S. aureus Smith            Oral    >16                         8-16                           12 >8 >16                                    >16                                       >16                                          >16                                             >16                                                0.74    (Sens)  Intraveneous                    0.5-1                       0.5-1                           0.67                              0.46                                 0.5-1                                    1-2                                       1-2                                           >4                                             NT 0.37    Escherichia coli            Intraveneous                    NT NT  NT 1.6                                 NT NT NT NT NT >32    UBMS 90-4    (Tet M)    __________________________________________________________________________

                                      TABLE V    __________________________________________________________________________    In Vitro Activity of CC and Comparative Antibiotics vs Recent Clinical    and Veterinary Isolates                       MIC (μg/ml) Range    Organism     [# Isolates]                       CC    U       T    __________________________________________________________________________    Staphylococcus aureus,                 [15]  0.12-4                             0.06-4  0.25->64    (methicillin-resistant)    Staphylococcus aureus,                 [15]  0.06-0.25                             0.03-0.12                                     0.12-1    (methicillin-susceptible)    Staphylococcus                 [16]  0.06-16                             0.03-1  0.12->64    Coagulase-negative,    (methicillin-resistant)    Staphylococcus                 [14]  0.06-4                             0.015-0.25                                     0.12->64    Coagulase-negative,    (methicillin-susceptible)    Enterococcus faecalis                 [10]  0.03-0.25                             0.03-16 0.12-64    Enterococcus faecium                 [10]  0.06-0.5                             0.03-16 0.12-64    Enterococcus spp.                 [8]   0.03-0.12                             0.03-16 0.12->64    (Vancomycin-resistant)    Streptococcus pyogenes                 [10]  0.06-0.12                             0.03-2  0.12-16    Streptococcus agalactiae                 [10]  0.12-0.25                             0.12-16 0.25-64    Streptococcus pneumoniae                 [10]  0.03-0.5                             0.06-0.5                                     0.12-2    Listeria monocytogenes                 [8]   0.06-0.12                             0.015-0.03                                     0.12-0.5    Escherichia coli                 [30]  0.25-4                             0.25-32 0.5->64    Escherichia coli                 [15]  0.25-4                             1-16    2->64    (Veterinary)    Shigella spp.                 [14]  0.12-0.5                             0.25-8  0.25->64    Klebsiella pneumoniae                 [10]  0.25-4                             0.5-8   0.5->64    Klebsiella oxytoca                 [10]  0.25-1                             0.5-4   0.5-1    Citrobacter freundii                 [10]  0.5-8 0.03-32 0.5-16    Citrobacter diversus                 [10]  0.25-1                             0.25-4  0.5-4    Salmonella spp.                 [11]  0.25-0.5                             0.5-16  0.5->64    Salmonella choleraesuis                 [15]  0.5-8 2->64   1->64    (Veterinary)    Serratia marcescens                 [10]  2-8   1-8     8->64    Enterobacter cloacae                 [10]  0.5-1 0.25-4  0.5-2    Enterobacter aerogenes                 [10]  0.25-1                             0.5-1   0.5-1    Providencia spp.                 [13]  1-8   4->64   1->64    Proteus mirabilis                 [26]  0.12-2                             1-32    0.5-64    Proteus vulgaris                 [18]  0.06-1                             0.5-16  0.25-64    Morganella morganii                 [16]  0.5-1 0.25-32 0.25->64    Pseudomonas aeruginosa                 [10]  2-16  1-16    2-32    Xanthamonas maltophilia                 [10]  1-8   0.12-1  8-16    Moraxella catarrhalis                 [18]  0.06-0.12                             0.03-0.12                                     0.06-0.5    Neisseria gonorrhoeae                 [14]  0.5-1 0.5-64  1->64    Haemophilus influenzae                 [15]  1-2   0.5-2   1-32    Pasturella multocida                 [17]  0.03-0.25                             0.015-4 0.06-16    (Veterinary)    Bordetella bronchiseptica                 [10]  0.06-0.12                             0.06-0.12                                     0.12-0.25    (Veterinary)    Bacteroides fragiles                 [11]  0.25-1                             <0.008-16                                     0.25->64    Bacteroides fragiles group                 [10]  0.12-2                             <0.008-4                                     0.25-32    Bacteroides spp.                 [9]   0.12-0.5                             0.03-16 0.25->64    Clostridium difficile                 [12]  0.06-0.12                             0.015-16                                     0.12-32    Clostridium perfringens                 [16]  0.03-2                             <0.008-16                                     0.015-16    Clostridium spp.                 [9]   0.03-0.12                             <0.008-16                                     0.015-64    Anaerobic    [15]  0.015-0.12                             0.05-8  4->64    Gram (+) Cocci    __________________________________________________________________________

EXAMPLE 1[4S-(4alpha,12aalpha)]-9-[(Bromoacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideMonohydrochloride and[4S-(4alpha,12aalpha)]-9-[(Chloroacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideMonohydrochloride

To a room temperature solution of 1.58 g of9-amino-6-demethyl-6-deoxytetracycline monosulfate, 20 ml of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, hereinafter calledDMPU, and 4 ml of acetonitrile is added 0.50 g of sodium carbonate. Themixture is stirred for 5 minutes followed by the addition of 0.942 g ofbromoacetyl chloride. The reaction is stirred for 1 hour, filtered, andthe filtrate added dropwise to a mixture of 50 ml of isopropanol and 500ml of diethyl ether. The resulting solid is collected, washed first withthe mixed solvent (isopropanol and diethyl ether) followed by diethylether, and dried to give 1.62 g of a mixture of the desired products.

MS(FAB): m/z 550 (M+H) and 506 (M+H).

EXAMPLE 2[4S-(4alpha,12aalpha)]-9-[(Bromoacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideMonohydrobromide

The title compound is prepared by the procedure of Example 1 using 1.2 gof bromoacetyl bromide to give 1.49 g of the pure desired product.

¹ H NMR(D₆ -DMSO): δ 12.1(s,1H), 9.9(bs,1H), 9.8(s,1H), 9.55(s,1H),9.05(s,1H), 8.05(d,1H), 6.8(d,1H), 4.3(s,1H), 4.2(s,2H) , 2.75(s,6H).

EXAMPLE 3[4S-(4alpha,12aalpha)]-9-[(Bromoacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideMonosulfate

To a room temperature solution of 1.05 g of9-amino-6-demethyl-6-deoxytetracycline monosulfate, 10 ml of DMPU and 2ml of acetonitrile is added 0.605 g of bromoacetyl bromide. The mixtureis stirred for 30 minutes, then poured slowly into a mixture of 5 mlmethyl alcohol, 50 ml isopropyl alcohol and 500 ml of diethyl ether. Theresulting yellow solid is collected, washed several times with diethylether and dried to give 1.27 g of the desired product.

¹ H NMR(D₆ -DMSO): δ 12.1(s,1H), 9.9(bs,1H), 9.8(s,1H), 9.55(s,1H),9.05(s,1H), 8.05(d,1H), 6.8(d,1H), 4.3(s,1H), 4.2(s,2H), 2.75(s,6H).

EXAMPLE 4[4S-(4alpha,12aalpha)]-9-[(Chloroacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideMonohydrochloride

To a room temperature solution of 0.0465 g of9-amino-6-demethyl-6-deoxytetracycline hydrochloride, 1.5 ml of DMPU and0.5 ml of acetonitrile is added 0.023 g of chloroacetyl chloride. Themixture is stirred for 30 minutes, then poured into a mixture of 0.5 mlof methyl alcohol, 2 ml of isopropyl alcohol and 20 ml of diethyl ether.The resulting solid is collected, washed with diethyl ether and dried togive 0.042 g of the desired product.

MS(FAB): m/z 506 (M+H). ¹ H NMR(D₆ -DMSO): δ 12.1(s,1H), 10.4(bs,1H),9.75(s,1H), 9.55(s,1H), 9.05(s,1H), 8.05(d,1H), 6.8(d,1H), 4.4(s,2H),4.3(s,1H), 2.8(s,6H).

EXAMPLE 5[4S-(4alpha,12aalpha)]-9-[(2-Bromo-1-oxopropyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideMonohydrobromide

The title compound is prepared by the procedure of Example 1, using 2.11g of 9-amino-4-(dimethylamino)-6-demethyl-6-deoxytetracyclinemonosulfate, 0.7 g of sodium carbonate, 20 ml of DMPU, ml ofacetonitrile and 1.73 g of 2-bromopropionyl bromide. The reaction isstirred for 1 hour to give 1.75 g of the desired product. This reactionworks equally well without sodium carbonate.

MS (FAB): m/z 564 (M+H).

EXAMPLE 6[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[(hexylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideDihydrochloride

A mixture of 0.23 g of product from Example 2, 0.80 g of n-hexylamineand 5 ml of DMPU, under argon, is stirred at room temperature for 2hours. The reaction is concentrated in vacuo and the residue dilutedwith a small volume of methanol. The diluted reaction solution is addeddropwise to a mixture of 10 ml of isopropyl alcohol and 100 ml ofdiethyl ether. 2M hydrochloric acid in diethyl ether is added until ayellow solid is observed. The resulting solid is collected, washed withdiethyl ether and dried to give 0.14 g of the desired product.

MS(FAB): m/z 571 (M+H).

Substantially following the methods described in detail herein above inExample 6, the compounds of this invention listed below in Examples 7-22are prepared.

    __________________________________________________________________________    Example                  Starting Material      MS(FAB):    #    Name                Prod. of Exp.                                      Reactant Rx Time                                                    m/z    __________________________________________________________________________     7   [4S-(4alpha,12aalpha)]-4-(dimethyl-                             2        Methylamine                                               2.5                                                 hrs.                                                    501(M + H)         amino)-1,4,4a,5,5a,6,11,12a-octahydro-                                      (40% in water)         3,10,12,12a-tetrahydroxy-9-[[(methyl-         amino)acetyl]amino]-1,11-dioxo-2-         naphthacenecarboxamide dihydrochloride     8   [4S-(4alpha,12aalpha)]-4-(Dimethyl-                             2        Ethylamine                                               0.5                                                 hr.                                                    515(M + H)         amino)-9-[[(ethylamino)acetyl]amino]-                                      (70% in water)         1,4,4a,5,5a,6,11,12a-octahydro-3,10,-         12,12a-tetrahydroxy-1,11-dioxo-2-         naphthacenecarboxamide dihydrochloride     9   [7S-(7alpha,10aalpha)]-N-[9-(Amino-                             2        Pyrrolidine                                               0.5                                                 hr.                                                    541(M + H)         carbonyl)-7-(dimethylamino)-5,5a,6,6a,-         7,10,10a,12-octahydro-1,8,10a,11-tetra-         hydroxy-10,12-dioxo-2-naphthacenyl]-1-         pyrrolidineacetamide dihydrochloride    10   [7S-(7alpha,10aalpha)]-N-[9-(Aminocar-                             2        4-Methyl-                                               1.5                                                 hr.                                                    569(M 30  H)         bonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,-                                      piperidine         10a,12-octahydro-1,8,10a,11-tetrahydroxy-         10,12-dioxo-2-naphthacenyl]-4-methyl-1-         piperidineacetamide dihydrochloride    11   [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-                             2        Propylamine                                               1 hr.                                                    529(M + H)         1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-         tetrahydroxy-1,11-dioxo-9-[[(propylamino)-         acetyl]amino]-2-naphthacenecarboxamide         dihydrochloride    12   [4S-(4alpha,12aalpha)]-9-[[(Butyl-                             1 or 3   n-Butylamine                                               2 hr.                                                    543(M + H)         amino)acetyl]amino]-4-(dimethyl-         amino)-1,4,4a,5,5a,6,11,12a-octa-         hydro-3,10,12,12a-tetrahydroxy-1,11-         dioxo-2-naphthacenecarboxamide di-         hydrochloride    13   [4S-(4alpha,12aalpha)]-4-(Dimethyl-                             5        Dimethylamine                                               2 hr.                                                    529(M + H)         amino)-9-[[2-(dimethylamino)-1-oxo-         propyl]amino]-1,4,4a,5,5a,6,11,12a-         octahydro-3,10,12,12a-tetrahydroxy-         1,11-dioxo-2-naphthacenecarboxamide         dihydrochloride    14   [4S-(4alpha,12aalpha)]-4-(Dimethyl-                             1        Amylamine                                               2 hr.                                                    557(M + H)         amino)-1,4,4a,5,5a,6,11,12a-octa-         hydro-3,10,12,12a-tetrahydroxy-1,11-         dioxo-9-[[(pentylamino)acetyl]amino]-         2-naphthacenecarboxamide monohydro-         chloride    15   [7S-(7alpha,10aalpha)]-N-9-(Aminocar-                             3        Piperidine                                               1 hr.                                                    555(M + H)         bonyl)-7-(dimethylamino)-5,5a,6,6a,7,-         10,10a,12-octahydro-1,8,10a,11-tetra-         hydroxy-10,12-dioxo-1-piperidine-         acetamide dihydrochloride    16   [4S-(4alpha,12aalpha)]-4-(Dimethyl-                             3        Benzylamine                                               1 hr.                                                    577(M + H)         amino)-1,4,4a,5,5a,6,11,12a-octa-         hydro-3,10,12,12a-tetrahydroxy-1,11-         dioxo-9-[[[(phenylmethyl)amino]-         acetyl]amino]2-naphthacenecarbox-         amide dihydrochloride    17   [4S-(4alpha,12aalpha)]-4-(Dimethyl-                             1        2-Thiophene-                                               11/2                                                 hr.                                                    583(M + H)         amino)-1,4,4a,5,5a,6,11,12a-octa-                                      methylamine         hydro-3,10,12,12a-tetrahydroxy-1,11-         dioxo-9-[[[(2-thienylmethyl)amino]-         acetyl]amino]-2-naphthacenecarboxamide         dihydrochloride    18   [4S-(4alpha,12aalpha)]-4-(Dimethyl-                             3        Isobutylamine                                               11/2                                                 hr.                                                    543(M + H)         amino)-1,4,4a,5,5a,6,11,12a-octa-         hydro-3,10,12,12a-tetrahydroxy-9-         [[[(2-methylpropyl)amino]acetyl]-         amino]-1,11-dioxo-2-naphthacenecar-         boxamide dihydrochloride    19   [4S-(4alpha,12aalpha)]-4-(Dimethyl-                             3        2-(Aminomethyl)                                               11/2                                                 hr.                                                    578(M + H)         amino)-1,4,4a,5,5a,6,11,12a-octa-                                      pyridine         hydro-3,10,12,12a-tetrahydroxy-1,11-         dioxo-9-[[[(2-pyridinylmethyl]amino]-         acetyl]amino]-2-naphthacenecarboxamide         dihydrochloride    20   [4S-(4alpha,12aalpha)]-9-[[(Diethyl-                             3        Diethylamine                                               11/2                                                 hr.                                                    543(M + H)         amino)acetyl]amino]-4-(dimethylamino)-         1,4,4a,5,5a,6,11,12a-octahydro-3,10,-         12,12a-tetrahydroxy-1,11-dioxo-2-         naphthacenecarboxamide dihydrochloride    21   [7S-(7alpha,10aalpha)]-N-9-(Aminocar-                             5        Pyrrolidine                                               1 hr.                                                    555(M + H)         bonyl)-7-(dimethylamino)-5,5a,6,6a,7,-         10,10a,12-octahydro-1,8,10a,11-tetra-         hydroxy-10,12-dioxo-2-naphthacenyl]-         alpha-methyl-1-pyrrolidinecarboxamide    22   [4S-(4alpha,12aalpha)]-9-[[[(Cyclo-                             3        (Aminomethyl)                                               1 hr.                                                    541(M + H)         propylmethyl)amino]acetyl]amino]-4-                                      cyclopropane         (dimethylamino)-1,4,4a,5,5a,6,11,12a-         tetrahydroxy-1,11-dioxo-2-naphthacene-         carboxamide dihydrochloride    __________________________________________________________________________

EXAMPLE 23[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideSulfate, Dihydrochloride, Monohydrochloride or Free Base

A mixture of 0.264 g of 9-amino-6-demethyl-6-deoxytetracycline, obtainedby literature procedures, 5 ml of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone, 2 ml of acetonitrileand 0.3 g of sodium carbonate is stirred at room temperature for 5minutes. To this mixture is added 0.094 g of N,N-dimethylglycyl chloridehydrochloride. The reaction is allowed to stir for 30 minutes at roomtemperature and then filtered. The filtrate is added dropwise toapproximately 300 ml of diethyl ether containing a few drop of eitherconcentrated sulfuric or hydrochloric acid. The resulting precipitate iscollected, washed with diethyl ether and dried to yield 0.12 g of thedesired product.

The hydrochloride salt is converted, by treatment with ammoniumhydroxide, to the free base.

MS (FAB): m/z 515 (M+H).

Alternatively, the title compound is prepared by the procedure ofExample 3, using 0.2 g of product from Example 1, 2, 3 or 4, 1.25 g ofdimethylamine (40% in water) and 5 ml of DMPU to give 0.14 g of thedesired product.

EXAMPLE 24 General Procedure for the Preparation of Mannich Bases

A mixture of 0.5 mm of product from Example 20 (free base), 3 ml oft-butyl alcohol, 0.55 mm of 37% formaldehyde, and 0.55 mm ofpyrrolidine, morpholine or piperidine is stirred at room temperature for30 minutes followed by heating at 100° C. for 15 minutes. The reactionmixture is cooled to room temperature and triturated with diethyl etherand hexane. The solid is collected, washed with diethyl ether andhexane, and dried to give the desired product. In this manner thefollowing compound is made:[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-N-(1-pyrrolidinylmethyl)-2-naphthacenecarboxamide

Substantially following the method described in Example 6, the compoundsof this invention listed below in Examples 25-48 are prepared using theproduct from Example 3 or 4.

EXAMPLE 25[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[(methoxyamino)acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 26[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[[(phenylmethoxy)amino]acetyl]amino]-2-naphthacenecarboxamideEXAMPLE 27[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-4-ethyl-1H-pyrazole-1-acetamideEXAMPLE 28[4S-(4alpha,12aalpha)]-9-[[(Cyclobutylmethylamino)acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 29[4S-(4alpha,12aalpha)]-9-[[(2-Butenylamino)acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 30[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[(hydroxyamino)acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 31[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[[methyl(phenylmethyl)amino]acetyl]amino]-2-naphthacenecarboxamideEXAMPLE 32[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-acetamideEXAMPLE 33[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-3-methyl-4-morpholineacetamideEXAMPLE 34[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-2-azabicyclo[2.2.1]heptane-2-acetamideEXAMPLE 35[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-6-methyl-2-azabicyclo[2.2.2]octane-2-acetamideEXAMPLE 36[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-1,12-dioxo-2-naphthacenyl]-4-methyl-1-piperazinecarboxamideEXAMPLE 37[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-4-hydroxy-1-piperazineacetamideEXAMPLE 38[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-3-methyl-1-piperazinecarboxamideEXAMPLE 39[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-3-cyclopropyltetrahydro-4H-thiazine-4-acetamideEXAMPLE 40[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-3-ethyl-1H-pyrrole-1-acetamideEXAMPLE 41[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[(1H-imidazol-2-ylmethylamino)acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 42[7S-(7alpha,10aalpha)]-N-[2-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]amino]-2-oxoethyl]alanineEXAMPLE 43[7S-(7alpha,10aalpha)]-N-[2-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl[-amino]-2-oxoethyl]carbamicacid 1,1-dimethylethyl ester EXAMPLE 44[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[[[(2-methylcyclopropyl)oxy]amino]acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 45[4S-(4alpha,12aalpha)]-9-[[[(Bicyclo[2.2.2]oct-2-yloxy)amino]acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 46 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[[(3-methyl-2-butenyl)amino]acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 47[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[[[4-[(2-methyl-1-oxopropyl)amino]phenyl]amino]acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 48[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-3-ethyl-1-pyrrolidineacetamide

Substantially following the method described in Example 6, the compoundsof this invention listed below in Examples 49-55 are prepared using theproduct from Example 5.

EXAMPLE 49[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[2-[[(1-methyl-1H-imidazol-2-yl)methyl]amino]-1-oxopropyl]amino]-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 50[4S-(4alpha,12aalpha)]-9-[[2-(Dicyclopropylamino)-1-oxopropyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 51[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-4-methoxy-α-methyl-1-piperazinecarboxamideEXAMPLE 52[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]tetrahydro-α,2-dimethyl-4H-1,4-thiazine-4-acetamideEXAMPLE 53[7S-(7alpha,10aalpha)]-[2-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]amino]-2-oxo-1-methylethyl]carbamicacid 2-propenyl Ester EXAMPLE 54[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-4-(aminomethyl)-α-methyl-1-piperidineacetamideEXAMPLE 55[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[2-[[3-(methylsulfonyl)phenyl]amino]-1-oxopropyl]amino]-1,11-dioxo-2-naphthacenecarboxamide

Substantially following the method, described in detail herein above inExample 5, the compound of invention Example 56 is prepared.

EXAMPLE 56[4S-(4alpha,12aalpha)]-9-[(2-Bromo-2-methyl-1-oxopropyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideHydrobromide EXAMPLE 57[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[2-methyl-2-(methylamino)-1-oxopropyl]amino]-1,11-dioxo-2-naphthacenecarboxamide

The titled compound is prepared by the procedure of Example 6. Thereactants are the product from Example 56 and methylamine.

EXAMPLE 58[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[2-(dimethylamino)-2-methyl-1-oxopropyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The titled compound is prepared by the procedure of Example 6. Thereactants are the product from Example 56 and dimethylamine.

Substantially following the method, described in detail herein above inExample 5, the compound of invention Example 59 is prepared.

EXAMPLE 59[4S-(4alpha,12aalpha)]-9-[(2-Bromo-1-oxobutyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideHydrobromide EXAMPLE 60[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[2-[[(3-methylcyclobutyl)oxy]amino]-1-oxobutyl]amino]-1,11-dioxo-2-naphthacenecarboxamideHydrobromide

The titled compound is prepared by the procedure of Example 6. Thereactants are the product from Example 59 and methylcyclobutyloxyamine.

EXAMPLE 61[4S-(4alpha,12aalpha)]-9-[[2-[(1,1-dimethylethyl)methylamino]-1-oxobutyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The titled compound is prepared by the procedure of Example 6. Thereactants are the product from Example 59 and N-methyl-t-butylamine.

EXAMPLE 62[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-.alpha.-ethyl-4-methyl-2-isoxazolidineacetamide

The titled compound is prepared by the procedure of Example 6. Thereactants are the product from Example 59 and 4-methyl-2-isoxazolidine.

EXAMPLE 63[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-.alpha.-ethyl-3-methyl-4H-1,2,4-triazole-4-acetamide

The titled compound is prepared by the procedure of Example 6. Thereactants are the product from Example 59 and 3-methyl-1,2,4-triazole.

Substantially following the method, described in detail herein above inExample 5, the compound of invention Example 64 is prepared.

EXAMPLE 64[4S-(4alpha,12aalpha)]-9-[(2-Bromo-1-oxopentyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideHydrobromide EXAMPLE 65[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[2-(dimethylamino)-3,3-dimethyl-1-oxobutyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The titled compound is prepared by the procedure of Example 6. Thereactants are the product from Example 64 and dimethylamine.

Substantially following the method, described in detail herein above inExample 5, the compound of invention Example 66 is prepared.

EXAMPLE 66[4S-(4alpha,12aalpha)]-9-[(2-Bromo-1-oxobutyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideHydrobromide EXAMPLE 67[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[2-(ethylamino)-2-methyl-1-oxobutyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The titled compound is prepared by the procedure of Example 6. Thereactants are the product from Example 66 and ethylamine.

Substantially following the method, described in detail herein above inExample 5, the compound of invention Example 68 is prepared.

EXAMPLE 68[4S-(4alpha,12aalpha)]-9-[(2-Bromo-3-hydroxy-1-oxopropyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideHydrobromide EXAMPLE 69[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[2-(dimethylamino)-3-hydroxy-1-oxopropyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The titled compound is prepared by the procedure of Example 6. Thereactants are the product from Example 68 and dimethylamine.

EXAMPLE 70[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-.alpha.-(hydroxymethyl)-4-methyl-1H-imidazole-1-acetamide

The titled compound is prepared by the procedure of Example 6. Thereactants are the product from Example 68 and 4-methylimidazole.

Substantially following the method, described in detail herein above inExample 5, the compound of invention Example 71 is prepared.

EXAMPLE 71[4S-(4alpha,12aalpha)]-9-[(2-Bromo-3-mercapto-1-oxopropyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideHydrobromide EXAMPLE 72[4S-(4alpha,12aalpha)]-9-[[2-(Diethylamino)-3-mercapto-1-oxopropyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The titled compound is prepared by the procedure of Example 6. Thereactants are the product from Example 71 and diethylamine.

EXAMPLE 73[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10-12-dioxo-2-naphthacenyl]-.alpha.-(mercaptomethyl)-1-piperazineacetamide

Substantially following the method, described in detail herein above inExample 5, the compound of invention Example 74 is prepared.

EXAMPLE 74[7S-(7alpha,10aalpha)]-4-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10-12-dioxo-2-naphthacenyl]amino]-3-bromo-4-oxobutanoicAcid Hydrobromide EXAMPLE 75[7S-(7alpha,10aalpha]-4-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-dioxo-2-naphthacenyl]amino]-3-(hexylamino)-4-oxobutanoicAcid

The titled compound is prepared by the procedure by Example 6. Thereactants are the product from Example 74 and n-hexylamine.

EXAMPLE 76[7S-(7alpha,10aalpha)]-4-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a-6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-1,12-dioxo-2-naphthacenyl]amino]tetrahydro-6-(hydroxymethyl)-2H-1,2-isoxazine-2-propanoicAcid

The titled compound is prepared by the procedure of Example 6. Thereactants are the product from Example 74 and6-(hydroxymethyl)-1,2-isoxazine.

EXAMPLE 77[7S-(7alpha,10aalpha)]-4-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]amino]-3-[ethyl(phenylmethyl)amino]-4-oxobutanoicAcid

The titled compound is prepared by the procedure of Example 6. Thereactants are the product from Example 74 and N-ethylbenzylamine.

Substantially following the method, described in detail herein above inExample 5, the compound of invention Example 78 is prepared.

EXAMPLE 78[7S-(7alpha,10aalpha)]-5-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a-11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]amino]-4-bromo-5-oxopentanoicAcid Hydrobromide EXAMPLE 79[7S-(7alpha,10aalpha)]-5-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]amino]-4-(cyclopropylamino)-5-oxopentanoicAcid

The titled compound is prepared by procedure of Example 6. The reactantsare the product from Example 78 and cyclopropylamine.

Substantially following the method, described in detail herein above inExample 5, the compound of invention Example 80 is prepared.

EXAMPLE 80[4S-(4alpha,12aalpha)]-9-[(Bromophenylacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideHydrobromide EXAMPLE 81[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[2-(dimethylamino)-2-phenylacetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1-11-dioxo-2-naphthacenecarboxamide

The titled compound is prepared by the procedure of Example 6. Thereactants are the product from Example 80 and dimethylamine.

Substantially following the method, described in detail herein above inExample 5, the compound of invention Example 82 is prepared.

EXAMPLE 82[4S-(4alpha,12aalpha)]-9-[[Bromo(4-hydroxyphenyl)acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideHydrobromide EXAMPLE 83 [4S-(4alpha,12aalpha)]-9-[[(Butylamino)(4-hydroxyphenyl)acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The titled compound is prepared by the procedure of Example 6. Thereactants are the product from Example 80 and dimethylamine.

Substantially following the method, described in detail herein above inExample 5, the compound of invention Example 84 is prepared.

EXAMPLE 84[4S-(4alpha,12aalpha)]-9-[[Bromo(4-methoxyphenyl)acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideHydrobromide EXAMPLE 85[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[2-(dimethylamino)-3-(4-methoxyphenyl)-1-oxopropyl]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1-11-dioxo-2-naphthacenecarboxamide

The titled compound is prepared by the procedure of Example 6. Thereactants are the product from Example 84 and dimethylamine.

Substantially following the method, described in detail herein above inExample 5, the compound of invention Example 86 is prepared.

EXAMPLE 86[4S-(4alpha,12aalpha)]-9-[[Bromo[4-(trifluoromethyl)phenyl]acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideHydrobromide EXAMPLE 87[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[2-(ethylmethylamino)-3-[4-(trifluoromethyl)phenyl]-1-oxopropyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The titled compound is prepared by the procedure ofxample 6. Thereactants are the product from Example 86 and N-ethylmethylamine.

Substantially following the method, described in detail herein above inExample 5, the compound of invention Example 88 is prepared.

EXAMPLE 88[4S-(4alpha,12aalpha)]-9-[[Bromo[4-(dimethylamino)phenyl]acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideHydrobromide EXAMPLE 89[4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[[4-(dimethylamino)phenyl](2-propenylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The titled compound is prepared by the procedure of Example 6. Thereactants are the product from Example 88 and N-allylamine.

We claim:
 1. A compound of the formula: ##STR28## wherein: Y is selectedfrom (CH₂)_(n) X, n=0-5, X is halogen selected from bromine, chlorine,fluorine and iodine;R is selected from hydrogen; straight or branched(C₁ -C₈)alkyl group selected from methyl, ethyl, propyl, isopropyl,butyl, isobutyl, pentyl, hexyl, heptyl and octyl; α-mercapto(C₁-C₄)alkyl group selected from mercaptomethyl, α-mercaptoethyl,α-mercapto-1-methylethyl, α-mercaptopropyl and α-mercaptobutyl;α-hydroxy(C₁ -C₄)alkyl group selected from hydroxymethyl,α-hydroxyethyl, α-hydroxy-1-methylethyl, α-hydroxypropyl andα-hydroxybutyl; carboxyl(C₁ -C₈)alkyl group; (C₆ -C₁₀)aryl groupselected from phenyl, α-naphthyl and β-naphthyl; substituted(C₆-C₁₀)aryl group wherein the substitution is selected from hydroxy,halogen, (C₁ -C₄)alkoxy, trihalo(C₁ -C₃) alkyl, nitro, amino, cyano, (C₁-C₄)alkoxycarbonyl, (C₁ -C₃)alkylamino and carboxy; (C₇ -C₉)aralkylgroup selected from benzyl, 1-phenylethyl, 2-phenylethyl andphenylpropyl; substituted(C₇ -C₉)aralkyl group wherein the substitutionselected from halo, (C₁ -C₄)alkyl, nitro, hydroxy, amino, mono- ordi-substituted (C₁ -C₄)alkylamino, (C₁ -C₄)alkoxy, (C₁-C₄)alkylsulfonyl, cyano and carboxy; R¹ is selected from hydrogen and(C₁ -C₆)alkyl selected from methyl, ethyl, propyl, isopropyl, butyl,isobutyl, pentyl and hexyl; when R does not equal R¹ the stereochemistryof the asymmetric carbon (i.e. the carbon bearing the Y substituent)maybe be either the racemate (DL) or the individual enantiomers (L orD); or a pharmacologically acceptable organic or inorganic salt or metalcomplex thereof.
 2. The compound according to claim 1, wherein:Y isselected from (CH₂)_(n) X, n=0-5, X is halogen selected from bromine,chlorine, fluorine and iodine; R is selected from hydrogen; straight orbranched (C₁ -C₈)alkyl group selected from methyl, ethyl, propyl,isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl and octyl;α-mercapto(C₁ -C₄)alkyl group selected from mercaptomethyl,α-mercaptoethyl, α-mercapto-1-methylethyl, α-mercaptopropyl andα-mercaptobutyl; α-hydroxy(C₁ -C₄)alkyl group selected fromhydroxymethyl, α-hydroxyethyl, α-hydroxy-1-methylethyl, α-hydroxypropyland α-hydroxybutyl; carboxyl(C₁ -C₈)alkyl group; (C₆ -C₁₀)aryl groupselected from phenyl, α-naphthyl and β-naphthyl; (C₇ -C₉)aralkyl groupselected from benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl;substituted (C₇ -C₉)aralkyl group wherein the substitution is selectedfrom halo, (C₁ -C₄)alkyl, nitro, hydroxy, amino, mono- or di-substituted(C₁ -C₄)alkylamino, (C₁ -C₄)alkoxy, (C₁ -C₄) alkylsulfonyl, cyano andcarboxy; R¹ is selected from hydrogen and (C₁ -C₆)alkyl selected frommethyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl;when R does not equal R¹ the stereochemistry of the asymmetric carbon(i.e. the carbon bearing the Y substituent) maybe be either the racemate(DL) or the individual enantiomers (L or D); or a pharmacologicallyacceptable organic or inorganic salt or metal complex thereof.
 3. Thecompound according to claim 1, wherein:Y is selected from (CH₂)_(n) X,n=0-5, X is halogen selected from bromine, chlorine, fluorine andiodine; R is selected from hydrogen; straight or branched (C₁ -C₈)alkylgroup selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl,pentyl, hexyl, heptyl and octyl; α-mercapto(C₁ -C₄)alkyl group selectedfrom mercaptomethyl, α-mercaptoethyl, α-mercapto-1-methylethyl andα-mercaptopropyl; α-hydroxy(C₁ -C₄)alkyl group selected fromhydroxymethyl, α-hydroxyethyl, α-hydroxy-1-methylethyl andα-hydroxypropyl; carboxyl(C₁ -C₈)alkyl group; (C₆ -C₁₀)aryl groupselected from phenyl, α-naphthyl and β-naphthyl; (C₇ -C₉)aralkyl groupselected from benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl; R¹is selected from hydrogen and (C₁ -C₆)alkyl selected from methyl, ethyl,propyl, isopropyl, butyl, isobutyl, pentyl and hexyl; when R does notequal R¹ the stereochemistry of the asymmetric carbon (i.e. the carbonbearing the Y substituent) maybe be either the racemate (DL) or theindividual enantiomers (L or D); or a pharmacologically acceptableorganic or inorganic salt or metal complex thereof.
 4. The compoundaccording to claim 1, wherein:Y is selected from (CH₂)_(n) X, n=0-5, Xis halogen selected from bromine, chlorine, fluorine and iodine; R isselected from hydrogen; straight or branched (C₁ -C₂)alkyl groupselected from methyl and ethyl; R¹ is selected from hydrogen and (C₁-C₂)alkyl selected from methyl and ethyl; when R does not equal R¹ thestereochemistry of the asymmetric carbon (i.e. the carbon bearing the Ysubstituent) maybe be either the racemate (DL) or the individualenantiomers (L or D); or a pharmacologically acceptable organic orinorganic salt or metal complex thereof.
 5. The compound according toclaim 1 wherein said inorganic salts comprise hydrochloric, hydrobromic,hydroiodic, phosphoric, nitric or sulfate.
 6. The compound according toclaim 1 wherein said organic salts comprise acetate, benzoate, citrate,cysteine or other amino acid, fumarate, glycolate, maleate, succinate,tartrate, alkylsulfonate or arylsulfonate.
 7. The compound according toclaim 1 wherein said metal complexes comprise aluminum, calcium, iron,magnesium, manganese or complex salts.
 8. A compound according to claim1, which is[4S-(4alpha,12aalpha)]-9-[(bromoacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidemonohydrochloride.
 9. A compound according to claim 1, which is[4S-(4alpha,12aalpha)]-9-[(chloroacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidemonohydrochloride.
 10. A compound according to claim 1, which is[4S-(4alpha,12aalpha)]-9-[(bromoacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidemonohydrobromide.
 11. A compound according to claim 1, which is[4S-(4alpha,12aalpha)]-9-[(bromoacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12.12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidemonosulfate.
 12. A compound according to claim 1, which is[4S-(4alpha,12aalpha)]-9-[(2-bromo-1-oxopropyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10-12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidemonohydrobromide.
 13. A compound according to claim 1, which is[4S-(4alpha,12aalpha)]-9-[(2-Bromo-2-methyl-1-oxopropyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrobromide.
 14. A compound according to claim 1, which is[4S-(4alpha,12aalpha)]-9-[(2-Bromo-1-oxobutyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrobromide.
 15. A compound according to claim 1, which is[4S-(4alpha,12aalpha)]-9-[(2-Bromo-1-oxopentyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrobromide.
 16. A compound according to claim 1, which is[4S-(4alpha,12aalpha)]-9-[(2-Bromo-1-oxobutyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrobromide.
 17. A compound according to claim 1, which is[4S-(4alpha,12aalpha)]-9-[(2-Bromo-3-hydroxy-1-oxopropyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrobromide.
 18. A compound according to claim 1, which is[4S-(4alpha,12aalpha)]-9-[(2-Bromo-3-mercapto-1-oxopropyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrobromide.
 19. A compound according to claim 1, which is[7S-(7alpha,10aalpha)]-4-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10-12-dioxo-2-naphthacenyl]amino]-3-bromo-4-oxobutanoicacid hydrobromide.
 20. A compound according to claim 1, which is[7S-(7alpha,10aalpha)]-5-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a-11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]amino]-4-bromo-5-oxopentanoicacid hydrobromide.
 21. A compound according to claim 1, which is[4S-(4alpha,12aalpha)]-9-[(Bromophenylacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrobromide.
 22. A compound according to claim 1, which is[4S-(4alpha,12aalpha)]-9-[[Bromo(4-hydroxyphenyl)acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrobromide.
 23. A compound according to claim 1, which is[4S-(4alpha,12aalpha)]-9-[[Bromo(4-methoxyphenyl)acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrobromide.
 24. A compound according to claim 1, which is[4S-(4alpha,12aalpha)]-9-[[Bromo[4-(trifluoromethyl)phenyl]acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrobromide.
 25. A compound according to claim 1, which is[4-S-(4alpha,12aalpha)]-9-[[Bromo[4-(dimethylamino)phenyl]acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrobromide.